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de Oliveira Silva Pinto M, de Paula Pereira L, de Mendonça Angelo ALP, Xavier MAP, de Magalhães Vieira Machado A, Castro Russo R. Dissecting the COVID-19 Immune Response: Unraveling the Pathways of Innate Sensing and Response to SARS-CoV-2 Structural Proteins. J Mol Recognit 2025; 38:e70002. [PMID: 39905998 DOI: 10.1002/jmr.70002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/08/2024] [Revised: 01/15/2025] [Accepted: 01/22/2025] [Indexed: 02/06/2025]
Abstract
Severe acute respiratory syndrome coronavirus (SARS-CoV), the virus responsible for COVID-19, interacts with the host immune system through complex mechanisms that significantly influence disease outcomes, affecting both innate and adaptive immunity. These interactions are crucial in determining the disease's severity and the host's ability to clear the virus. Given the virus's substantial socioeconomic impact, high morbidity and mortality rates, and public health importance, understanding these mechanisms is essential. This article examines the diverse innate immune responses triggered by SARS-CoV-2's structural proteins, including the spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins, along with nonstructural proteins (NSPs) and open reading frames. These proteins play pivotal roles in immune modulation, facilitating viral replication, evading immune detection, and contributing to severe inflammatory responses such as cytokine storms and acute respiratory distress syndrome (ARDS). The virus employs strategies like suppressing type I interferon production and disrupting key antiviral pathways, including MAVS, OAS-RNase-L, and PKR. This study also explores the immune pathways that govern the activation and suppression of immune responses throughout COVID-19. By analyzing immune sensing receptors and the responses initiated upon recognizing SARS-CoV-2 structural proteins, this review elucidates the complex pathways associated with the innate immune response in COVID-19. Understanding these mechanisms offers valuable insights for therapeutic interventions and informs public health strategies, contributing to a deeper understanding of COVID-19 immunopathogenesis.
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Affiliation(s)
- Matheus de Oliveira Silva Pinto
- Laboratory of Pulmonary Immunology and Mechanics, Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
- Viral Disease Immunology Group, Fundação Osvaldo Cruz, Instituto René Rachou, Belo Horizonte, Minas Gerais, Brazil
| | - Leonardo de Paula Pereira
- Laboratory of Pulmonary Immunology and Mechanics, Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
- Viral Disease Immunology Group, Fundação Osvaldo Cruz, Instituto René Rachou, Belo Horizonte, Minas Gerais, Brazil
| | | | | | | | - Remo Castro Russo
- Laboratory of Pulmonary Immunology and Mechanics, Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
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Zhang B, Zhang P, Wang H, Wang X, Hu Z, Wang F, Li Z. Dual Protein Corona-Mediated Target Recognition System for Visual Detection and Single-Molecule Counting of Nucleic Acids. ACS NANO 2025; 19:6929-6941. [PMID: 39951551 DOI: 10.1021/acsnano.4c13924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 02/16/2025]
Abstract
Rapid, highly sensitive, and specific nucleic acid detection plays a crucial role in advancing point-of-care (POC) diagnostics for pathogens and viruses, cancer monitoring, and optimizing clinical treatments. Herein, leveraging the precise recognition ability of CRISPR/dCas9 and the powerful localized surface plasmon resonance (LSPR) of gold nanoparticles (AuNPs), we report the design of a dual protein corona-mediated detection platform to simultaneously fulfill rapid POC testing and single-molecule counting of nucleic acids in a one-pot and one-step manner. This system uses guide RNA as a molecular bridge to anchor dCas9 protein onto AuNPs, forming artificial protein coronas. Upon recognizing a target, the interaction between the two protein coronas on the same nucleic acid molecule triggers cross-linked aggregation of AuNPs. Then, a target as low as 100 aM can be visually detected within 30 min, making the platform particularly well-suited for rapid POC application and the screening of emerging epidemics. Additionally, the superior LSPR properties of AuNPs increase the light-scattering signal generated during target-induced aggregation, enabling the visualization of the aggregated AuNPs as diffraction-limited spots under confocal microscopy. By counting these spots, the platform achieves unprecedented detection sensitivity, identifying a target as low as 1 aM, which is equivalent to just 6 molecules in a 10 μL system, demonstrating single-molecule detection capability. This dual protein corona-mediated detection system offers exceptional promise for large-scale screening of pathogenic viruses and the early detection of cancer, particularly in applications requiring ultrahigh sensitivity at the single-molecule level.
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Affiliation(s)
- Baoshui Zhang
- Beijing Key Laboratory for Bioengineering and Sensing Technology, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, 30 Xueyuan Road, Haidian District, Beijing 100083, China
| | - Pengbo Zhang
- Beijing Key Laboratory for Bioengineering and Sensing Technology, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, 30 Xueyuan Road, Haidian District, Beijing 100083, China
| | - Hao Wang
- Beijing Key Laboratory for Bioengineering and Sensing Technology, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, 30 Xueyuan Road, Haidian District, Beijing 100083, China
| | - Xiaoyu Wang
- School of Materials Science and Engineering, University of Science and Technology Beijing, 30 Xueyuan Road, Haidian District, Beijing 100083, China
| | - Zhian Hu
- Beijing Key Laboratory for Bioengineering and Sensing Technology, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, 30 Xueyuan Road, Haidian District, Beijing 100083, China
| | - Fangfang Wang
- College of Life Sciences, Hebei Agricultural University, Baodin 071001, China
| | - Zhengping Li
- Beijing Key Laboratory for Bioengineering and Sensing Technology, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, 30 Xueyuan Road, Haidian District, Beijing 100083, China
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Qudus MS, Afaq U, Liu S, Wu K, Yu C, Tian M, Wu J. SARS-CoV-2-ORF-3a Mediates Apoptosis Through Mitochondrial Dysfunction Modulated by the K + Ion Channel. Int J Mol Sci 2025; 26:1575. [PMID: 40004042 DOI: 10.3390/ijms26041575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/31/2024] [Revised: 01/21/2025] [Accepted: 01/22/2025] [Indexed: 02/27/2025] Open
Abstract
Coronavirus disease 2019 (COVID-19) causes pulmonary edema, which disrupts the lung alveoli-capillary barrier and leads to pulmonary cell apoptosis, the main cause of death. However, the molecular mechanism behind SARS-CoV-2's apoptotic activity remains unknown. Here, we revealed that SARS-CoV-2-ORF-3a mediates the pulmonary pathology associated with SARS-CoV-2, which is demonstrated by the fact that it causes lung tissue damage. The in vitro results showed that SARS-CoV-2-ORF-3a triggers cell death via the disruption of mitochondrial homeostasis, which is modulated through the regulation of Mitochondrial ATP-sensitive Potassium Channel (MitoKATP). The addition of exogenous Potassium (K+) in the form of potassium chloride (KCl) attenuated mitochondrial apoptosis along with the inflammatory interferon response (IFN-β) triggered by SARS-ORF-3a. The addition of exogenous K+ strongly suggests that dysregulation of K+ ion channel function is the central mechanism underlying the mitochondrial dysfunction and stress response induced by SARS-CoV-2-ORF-3a. Our results designate that targeting the potassium channel or its interactions with ORF-3a may represent a promising therapeutic strategy to mitigate the damaging effects of infection with SARS-CoV-2.
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Affiliation(s)
- Muhammad Suhaib Qudus
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Uzair Afaq
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Siyu Liu
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Kailang Wu
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Chen Yu
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Mingfu Tian
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Jianguo Wu
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
- Key Laboratory of Ministry of Education for Viral Pathogenesis & Infection Prevention and Control, Institute of Medical Microbiology, Jinan University, Guangzhou 510632, China
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Cao Z, Yang Y, Zhang S, Zhang T, Lü P, Chen K. Liquid-liquid phase separation in viral infection: From the occurrence and function to treatment potentials. Colloids Surf B Biointerfaces 2025; 246:114385. [PMID: 39561518 DOI: 10.1016/j.colsurfb.2024.114385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/02/2024] [Revised: 11/08/2024] [Accepted: 11/14/2024] [Indexed: 11/21/2024]
Abstract
Liquid-liquid phase separation (LLPS) of biomacromolecules, as a widespread cellular functional mechanism, is closely related to life processes, and is also commonly present in the lifecycle of viruses. Viral infection often leads to the recombination and redistribution of intracellular components to form biomacromolecule condensates assembled from viral replication-related proteins and intracellular components, which plays an important role in the process of viral infection. In this review, the key and influencing factors of LLPS are generalized, which mainly depend on various molecular interactions and environmental conditions in solution. Meanwhile, some examples of viruses utilizing LLPS are summarized, which are conducive to further understanding the subtle and complex biological regulatory processes between phase condensation and viruses. Finally, some representative antiviral drugs targeting phase separation that have been discovered are also outlined. In conclusion, in-depth study of the role of LLPS in viral infection is helpful to understand the mechanisms of virus-related diseases from a new perspective, and also provide a new therapeutic strategy for future treatments.
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Affiliation(s)
- Zhaoxiao Cao
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China
| | - Yanhua Yang
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China.
| | - Simeng Zhang
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China
| | - Tiancheng Zhang
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China
| | - Peng Lü
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China
| | - Keping Chen
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China
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Venkateshwarlu A, Akshayveer, Singh S, Melnik R. Piezoelectricity and flexoelectricity in biological cells: the role of cell structure and organelles. Biomech Model Mechanobiol 2025; 24:47-76. [PMID: 39455540 DOI: 10.1007/s10237-024-01895-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/22/2024] [Accepted: 09/25/2024] [Indexed: 10/28/2024]
Abstract
Living tissues experience various external forces on cells, influencing their behaviour, physiology, shape, gene expression, and destiny through interactions with their environment. Despite much research done in this area, challenges remain in our better understanding of the behaviour of the cell in response to external stimuli, including the arrangement, quantity, and shape of organelles within the cell. This study explores the electromechanical behaviour of biological cells, including organelles like microtubules, mitochondria, nuclei, and cell membranes. A two-dimensional bio-electromechanical model for two distinct cell structures has been developed to analyze the behavior of the biological cell to the external electrical and mechanical responses. The piezoelectric and flexoelectric effects have been included via multiphysics coupling for the biological cell. All the governing equations have been discretized and solved by the finite element method. It is found that the longitudinal stress is absent and only the transverse stress plays a crucial role when the mechanical load is imposed on the top side of the cell through compressive displacement. The impact of flexoelectricity is elucidated by introducing a new parameter called the maximum electric potential ratio ( V R , max ). It has been found that V R , max depends upon the orientation angle and shape of the microtubules. The magnitude of V R , max exhibit huge change when we change the shape and orientation of the organelles, which in some cases (boundary condition (BC)-3) can reach to three times of regular shape organelles. Further, the study reveals that the number of microtubules significantly impacts effective elastic and piezoelectric coefficients, affecting cell behavior based on structure, microtubule orientation, and mechanical stress direction. The insight obtained from the current study can assist in advancements in medical therapies such as tissue engineering and regenerative medicine.
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Affiliation(s)
- Akepogu Venkateshwarlu
- MS2Discovery Interdisciplinary Research Institute, Wilfrid Laurier University, 75 University Avenue West, Waterloo, ON, N2L 3C5, Canada.
| | - Akshayveer
- MS2Discovery Interdisciplinary Research Institute, Wilfrid Laurier University, 75 University Avenue West, Waterloo, ON, N2L 3C5, Canada
| | - Sundeep Singh
- Faculty of Sustainable Design Engineering, University of Prince Edward Island, Charlottetown, PE, C1A 4P3, Canada
| | - Roderick Melnik
- MS2Discovery Interdisciplinary Research Institute, Wilfrid Laurier University, 75 University Avenue West, Waterloo, ON, N2L 3C5, Canada
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Sultana A, Banu LA, Hossain M, Azmin N, Nila NN, Sinha SK, Hassan Z. Evaluation of Genomic Surveillance of SARS-CoV-2 Virus Isolates and Comparison of Mutational Spectrum of Variants in Bangladesh. Viruses 2025; 17:182. [PMID: 40006937 DOI: 10.3390/v17020182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/28/2024] [Revised: 12/19/2024] [Accepted: 12/22/2024] [Indexed: 02/27/2025] Open
Abstract
The SARS-CoV-2-induced disease, COVID-19, remains a worldwide public health concern due to its high rate of transmission, even in vaccinated and previously infected people. In the endemic state, it continues to cause significant pathology. To elu- cidate the viral mutational changes and screen the emergence of new variants of concern, we conducted this study in Bangladesh. The viral RNA genomes extracted from 25 ran- domly collected samples of COVID-19-positive patients from March 2021 to February 2022 were sequenced using Illumina COVID Seq protocol and genomic data processing, as well as evaluations performed in DRAGEN COVID Lineage software. In this study, the percentage of Delta, Omicron, and Mauritius variants identified were 88%, 8%, and 4%, respectively. All of the 25 samples had 23,403 A>G (D614G, S gene), 3037 C>T (nsp3), and 14,408 C>T (nsp12) mutations, where 23,403 A>G was responsible for increased transmis- sion. Omicron had the highest number of unique mutations in the spike protein (i.e., sub- stitutions, deletions, and insertions), which may explain its higher transmissibility and immune-evading ability than Delta. A total of 779 mutations were identified, where 691 substitutions, 85 deletions, and 3 insertion mutations were observed. To sum up, our study will enrich the genomic database of SARS-CoV-2, aiding in treatment strategies along with understanding the virus's preferences in both mutation type and mutation site for predicting newly emerged viruses' survival strategies and thus for preparing to coun- teract them.
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Affiliation(s)
- Abeda Sultana
- Department of Anatomy, Dhaka Medical College, Dhaka 1000, Bangladesh
| | - Laila Anjuman Banu
- Department of Anatomy, Dhaka Medical College, Dhaka 1000, Bangladesh
- Genetics and Molecular Biology Laboratory, Bangabandhu Sheikh Mujib Medical University, Dhaka 1000, Bangladesh
| | - Mahmud Hossain
- Laboratory of Neuroscience and Neurogenetics, Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka 1000, Bangladesh
| | - Nahid Azmin
- Department of Anatomy, Shahabuddin Medical College, Dhaka 1212, Bangladesh
| | - Nurun Nahar Nila
- Laboratory of Neuroscience and Neurogenetics, Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka 1000, Bangladesh
| | - Sharadindu Kanti Sinha
- Department of Pharmacology, Bangabandhu Sheikh Mujib Medical University, Dhaka 1000, Bangladesh
| | - Zahid Hassan
- Department of Physiology and Molecular Biology, Bangladesh University of Health Sciences, Dhaka 1216, Bangladesh
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Sacco MA, Gualtieri S, Princi A, Verrina MC, Carbone A, Tarda L, Ranno F, Gratteri S, Aquila I. Investigating the Post-Mortem Risk of Transmission of SARS-CoV-2 Virus in Cadaveric Tissues: A Systematic Review of the Literature. Microorganisms 2025; 13:284. [PMID: 40005651 DOI: 10.3390/microorganisms13020284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/19/2024] [Revised: 01/10/2025] [Accepted: 01/14/2025] [Indexed: 02/27/2025] Open
Abstract
The emergence of SARS-CoV-2, responsible for the COVID-19 pandemic, has prompted extensive research into its transmission dynamics; yet, a critical aspect that remains underexplored is the post-mortem infectivity of the virus within cadaveric tissues. Understanding the mechanisms by which SARS-CoV-2 maintains infectivity after death is essential, as it raises significant concerns regarding public health and forensic practices. Research indicates that the virus can persist in various tissues, including lung, liver, and kidney tissues, with studies showing that factors such as the time elapsed since death, the presence of underlying health conditions, and environmental conditions at the time of death can influence the level of infectivity in deceased individuals. These findings are not only crucial for establishing safety protocols for forensic investigators who handle cadavers but also for informing public health guidelines that govern the management of bodies during and after outbreaks. As we investigate the implications of post-mortem SARS-CoV-2 infectivity, it becomes imperative to establish comprehensive protocols to mitigate risks associated with the handling and disposal of infected bodies, thereby protecting public health and ensuring the safety of those working in forensic environments. This paper aims to elucidate the mechanisms of infectivity in cadaveric tissues, explore the persistence of the virus in various tissue types, and assess the broader implications for public health and forensic investigations, ultimately contributing to a safer approach in dealing with COVID-19-related fatalities.
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Affiliation(s)
- Matteo Antonio Sacco
- Institute of Legal Medicine, Department of Medical and Surgical Sciences, "Magna Graecia" University, 88100 Catanzaro, Italy
| | - Saverio Gualtieri
- Institute of Legal Medicine, Department of Medical and Surgical Sciences, "Magna Graecia" University, 88100 Catanzaro, Italy
| | - Aurora Princi
- Institute of Legal Medicine, Department of Medical and Surgical Sciences, "Magna Graecia" University, 88100 Catanzaro, Italy
| | - Maria Cristina Verrina
- Institute of Legal Medicine, Department of Medical and Surgical Sciences, "Magna Graecia" University, 88100 Catanzaro, Italy
| | - Angela Carbone
- Institute of Legal Medicine, Department of Medical and Surgical Sciences, "Magna Graecia" University, 88100 Catanzaro, Italy
| | - Lucia Tarda
- Institute of Legal Medicine, Department of Medical and Surgical Sciences, "Magna Graecia" University, 88100 Catanzaro, Italy
| | - Francesco Ranno
- Institute of Legal Medicine, Department of Medical and Surgical Sciences, "Magna Graecia" University, 88100 Catanzaro, Italy
| | - Santo Gratteri
- Institute of Legal Medicine, Department of Medical and Surgical Sciences, "Magna Graecia" University, 88100 Catanzaro, Italy
| | - Isabella Aquila
- Institute of Legal Medicine, Department of Medical and Surgical Sciences, "Magna Graecia" University, 88100 Catanzaro, Italy
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Varghese A, Liu J, Liu B, Guo W, Dong F, Patterson TA, Hong H. Analysis of Structures of SARS-CoV-2 Papain-like Protease Bound with Ligands Unveils Structural Features for Inhibiting the Enzyme. Molecules 2025; 30:491. [PMID: 39942596 PMCID: PMC11820935 DOI: 10.3390/molecules30030491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/17/2024] [Revised: 01/17/2025] [Accepted: 01/20/2025] [Indexed: 02/16/2025] Open
Abstract
The COVID-19 pandemic, driven by the novel coronavirus SARS-CoV-2, has drastically reshaped global health and socioeconomic landscapes. The papain-like protease (PLpro) plays a critical role in viral polyprotein cleavage and immune evasion, making it a prime target for therapeutic intervention. Numerous compounds have been identified as inhibitors of SARS-CoV-2 PLpro, with many characterized through crystallographic studies. To date, over 70 three-dimensional (3D) structures of PLpro complexed ligands have been deposited in the Protein Data Bank, offering valuable insight into ligand-binding features that could aid the discovery and development of effective COVID-19 treatments targeting PLpro. In this study, we reviewed and analyzed these 3D structures, focusing on the key residues involved in ligand interactions. Our analysis revealed that most inhibitors bind to PLpro's substrate recognition sites S3/S4 and SUb2. While these sites are highly attractive and have been extensively explored, other potential binding regions, such as SUb1 and the Zn(II) domain, are less explored and may hold untapped potential for future COVID-19 drug discovery and development. Our structural analysis provides insights into the molecular features of PLpro that could accelerate the development of novel therapeutics targeting this essential viral enzyme.
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Affiliation(s)
| | | | | | | | | | | | - Huixiao Hong
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA; (A.V.); (J.L.); (B.L.); (W.G.); (F.D.); (T.A.P.)
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9
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Morgan MA, Saleh SE, Salamoni AH, Alshahrani MY, Aboshanab KM. Hematological, inflammatory and serological responses among COVID-19 patients admitted to intensive care unit. Future Sci OA 2024; 10:2389664. [PMID: 39172714 PMCID: PMC11346553 DOI: 10.1080/20565623.2024.2389664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/25/2023] [Accepted: 08/05/2024] [Indexed: 08/24/2024] Open
Abstract
Aim: To correlate hematological, inflammatory indicators and serological responses among COVID-19 patients to point out the significant biomarkers for disease management and prognosis.Materials & methods: Standard analytical and molecular methods were used to assess various inflammatory and serological Responses among COVID-19 patients (ICU- (n = 99) and non-ICU patients (n = 64) as compared with health control (n = 40).Results: Significant differences in the Hb, WBC, Lymphocyte count, CRP and serum ferritin (p < 0.05) were observed. Patients' IgM/IgG antibodies against SARS-CoV-2 were associated with increased CRP, LDH and serum ferritin levels.Conclusion: A significant association between serum IgG/IgM and ICU admission was observed. Although serum ferritin and LDH can offer information about the extent of inflammation, they are exclusive factors for ICU admission.
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Affiliation(s)
- Mirette A Morgan
- External Quality Assurance Laboratory, Central Public Health of Laboratories CPHL, Ministry of Health, Cairo, 11613, Egypt
| | - Sarra E Saleh
- Department of Microbiology & Immunology, Faculty of Pharmacy, Ain Shams University, Cairo, 1566, Egypt
| | - Azza H Salamoni
- Microbiology & Immunology Department, Central Public Health, CPHL, Ministry of Health, Cairo, 11613, Egypt
- Egypt Center for Research & Regenerative Medicine, ECRRM, Cairo, 11517, Egypt
| | - Mohammad Y Alshahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, P.O. Box 61413, Abha, 9088, Saudi Arabia
| | - Khaled M Aboshanab
- Department of Microbiology & Immunology, Faculty of Pharmacy, Ain Shams University, Cairo, 1566, Egypt
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Faggioni G, Moramarco F, Luciano E, De Santis R, Amoroso A, Petralito G, Molinari F, Grosso P, Rozov O, Morelli D, Carbone D, Lista F. Quantitative IgG response to SARS-CoV-2 membrane protein in infected individuals strongly correlates with lung injury. Sci Rep 2024; 14:30665. [PMID: 39730423 DOI: 10.1038/s41598-024-78381-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/26/2024] [Accepted: 10/30/2024] [Indexed: 12/29/2024] Open
Abstract
The clinical manifestations of SARS-CoV-2 infection may range from asymptomatic or minor conditions to severe and life-threatening outcomes. The respiratory system is a principal target of the virus and in the majority of cases of severe disease, an acute form of pneumonia develops. Despite concerted global efforts to elucidate the pathogenic mechanisms of COVID-19, the progression of the infection leading to pulmonary damage remains poorly understood. The present study aimed to analyse the immunological profile of subjects with a previous SARS-CoV-2 infection and predisposition to lung injury. The results showed a strong correlation between IgG anti-membrane antibodies and lung injury.
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Affiliation(s)
| | | | | | | | | | | | | | - Paolo Grosso
- Italian Department of Defence, 00184, Rome, Italy
| | - Orr Rozov
- Food and Agriculture Organization, 00153, Rome, Italy
| | | | - Daniele Carbone
- Defence Institute for Biomedical Sciences, 00184, Rome, Italy
| | - Florigio Lista
- Defence Institute for Biomedical Sciences, 00184, Rome, Italy
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Anede N, Ouassaf M, Rengasamy KRR, Khan SU, Alhatlani BY. Identification and Evaluation of Natural Compounds as Potential Inhibitors of NS2B-NS3 Zika Virus Protease: A Computational Approach. Mol Biotechnol 2024:10.1007/s12033-024-01357-6. [PMID: 39733219 DOI: 10.1007/s12033-024-01357-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/26/2024] [Accepted: 12/11/2024] [Indexed: 12/30/2024]
Abstract
The Zika virus (ZIKV), an arbovirus within the Flavivirus genus, is associated with severe neurological complications, including Guillain-Barré syndrome in affected individuals and microcephaly in infants born to infected mothers. With no approved vaccines or antiviral treatments available, there is an urgent need for effective therapeutic options. This study aimed to identify new natural compounds with inhibitory potential against the NS2B-NS3 protease (PDB ID: 5LC0), an essential enzyme in viral replication. An e-pharmacophore model was generated using a five-point (ADDRR) feature approach in the PHASE module of Schrodinger and used for the virtual screening of 26,689 natural compounds from the PubChem database. The screening yielded 14,277 prioritized compounds based on fitness scores, further refined through extra precision (XP) docking in GLIDE, resulting in 24 compounds. Eight top hits were selected following ADME analysis with SwissADME, and toxicity screening with ProTox-II identified four non-toxic lead candidates. Molecular dynamic simulations confirmed the stability of the three most promising leads, CID 44418637, CID 163078083, and CID 68734190, with binding affinities of - 7.721, - 8.226, and - 8.307 kcal/mol, respectively. MM/GBSA analysis revealed that Compounds 68734190 (- 50.192 kcal/mol) and 163078083 (- 49.947 kcal/mol) possess superior binding affinities to the ZIKV NS2B-NS3 protease compared to the reference compound (- 38.347 kcal/mol). Given their natural origin, these compounds may offer safer options to mitigate severe ZIKV-related symptoms while providing a favourable safety and pharmacokinetic profile. This study lays the groundwork for developing targeted ZIKV therapies, potentially addressing a significant unmet need in public health by reducing the incidence of ZIKV-related complications. Further experimental validation is required to confirm efficacy and address potential development challenges.
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Affiliation(s)
- Nada Anede
- Group of Computational and Medicinal Chemistry, LMCE Laboratory, University of Biskra, Biskra, Algeria
| | - Mebarka Ouassaf
- Group of Computational and Medicinal Chemistry, LMCE Laboratory, University of Biskra, Biskra, Algeria
| | - Kannan R R Rengasamy
- Laboratory of Natural Products and Medicinal Chemistry (LNPMC), Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Thandalam, Chennai, 602105, India.
- Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa.
| | - Shafi Ullah Khan
- Normandie Univ, Université de Caen Normandie, Inserm U1086 ANTICIPE (Interdisciplinary Research Unit for Cancer Prevention and Treatment), 14076, Caen, France
- Comprehensive Cancer Center François Baclesse, UNICANCER, 14076, Caen, France
| | - Bader Y Alhatlani
- Unit of Scientific Research, Applied College, Qassim University, Buraydah, 52571, Saudi Arabia
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Queirós-Reis L, Alvites R, Maurício AC, Brancale A, Bassetto M, Mesquita JR. Disrupting SARS-CoV-2 Spike Protein Activity: A Virtual Screening and Binding Assay Study. Int J Mol Sci 2024; 26:151. [PMID: 39796007 PMCID: PMC11720127 DOI: 10.3390/ijms26010151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/24/2024] [Revised: 12/19/2024] [Accepted: 12/21/2024] [Indexed: 01/13/2025] Open
Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a respiratory virus that emerged in late 2019 and rapidly spread worldwide, causing the COVID-19 pandemic. The spike glycoprotein (S protein) plays a crucial role in viral target recognition and entry by interacting with angiotensin, converting enzyme 2 (ACE2), the functional receptor for the virus, via its receptor binding domain (RBD). The RBD availability for this interaction can be influenced by external factors, such as fatty acids. Linoleic acid (LA), a free fatty acid, has been shown to bind the S protein, modulating the viral infection by reducing initial target recognition. LA interacts with the fatty acid binding pocket (FABP), a potential drug target against SARS-CoV-2. In this study, we aimed to exploit the FABP as a drug target by performing a docking-based virtual screening with a library of commercially available, drug-like compounds. The virtual hits identified were then assessed in in vitro assays for the inhibition of the virus-host interaction and cytotoxicity. Binding assays targeting the spike-ACE2 interaction identified multiple compounds with inhibitory activity and low cytotoxicity.
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Affiliation(s)
- Luís Queirós-Reis
- Abel Salazar Institute of Biomedical Sciences (ICBAS), University of Porto, 4050-313 Porto, Portugal; (L.Q.-R.); (R.A.); (A.C.M.)
| | - Rui Alvites
- Abel Salazar Institute of Biomedical Sciences (ICBAS), University of Porto, 4050-313 Porto, Portugal; (L.Q.-R.); (R.A.); (A.C.M.)
- Animal Science Study Centre (CECA), University of Porto Agroenvironment, Technologies and Sciences Institute (ICETA), 4051-401 Porto, Portugal
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
- Advanced Polytechnic and University Cooperative, University Institute of Health Sciences (CESPU), Avenida Central de Gandra 1317, 4585-116 Gandra, Portugal
| | - Ana Colette Maurício
- Abel Salazar Institute of Biomedical Sciences (ICBAS), University of Porto, 4050-313 Porto, Portugal; (L.Q.-R.); (R.A.); (A.C.M.)
- Animal Science Study Centre (CECA), University of Porto Agroenvironment, Technologies and Sciences Institute (ICETA), 4051-401 Porto, Portugal
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
| | - Andrea Brancale
- Department of Organic Chemistry, University of Chemistry and Technology Prague, 166 28 Prague, Czech Republic;
| | - Marcella Bassetto
- School of Pharmacy and Pharmaceutical Sciences, College of Biomedical and Life Sciences, Cardiff University, Cardiff CF10 3BN, UK;
- Department of Chemistry, Faculty of Science and Engineering, Swansea University, Swansea SA2 8PP, UK
| | - João R. Mesquita
- Abel Salazar Institute of Biomedical Sciences (ICBAS), University of Porto, 4050-313 Porto, Portugal; (L.Q.-R.); (R.A.); (A.C.M.)
- Epidemiology Research Unit (EPIunit), Institute of Public Health, University of Porto, 4050-091 Porto, Portugal
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Rustagi V, Gupta SRR, Talwar C, Singh A, Xiao ZZ, Jamwal R, Bala K, Bhaskar AK, Nagar S, Singh IK. SARS-CoV-2 pathophysiology and post-vaccination severity: a systematic review. Immunol Res 2024; 73:17. [PMID: 39692912 DOI: 10.1007/s12026-024-09553-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/17/2024] [Accepted: 12/02/2024] [Indexed: 12/19/2024]
Abstract
Currently, COVID-19 is still striking after 4 years of prevalence, with millions of cases and thousands of fatalities being recorded every month. The virus can impact other major organ systems, including the gastrointestinal tract (GIT), cardiovascular, central nervous system, renal, and hepatobiliary systems. The resulting organ dysfunction from SARS-CoV-2 may be attributed to one or a combination of mechanisms, such as direct viral toxicity, disruptions in the renin-angiotensin-aldosterone system (RAAS), thrombosis, immune dysregulation, and ischemic injury due to vasculitis. SARS-CoV-2 vaccines effectively reduce the severity of the disease, hospitalizations, and mortality. As of October 2024, 13.58 billion vaccine doses have been administered, with an average of 6959 daily doses. Also, the boosters are given after the primary immunization in a homologous and heterologous manner. The vaccines imposed severe potential health side effects such as clotting or obstruction of blood vessels termed arterial or venous thrombosis, autoimmune damage of nerve cells (Guillain-Barré syndrome; GBS), intense activation of coagulation system (vaccine-induced thrombotic thrombocytopenia), acute ischemic stroke (AIS) and cerebral venous sinus thrombosis (CVST), myocarditis, pericarditis, and glomerular disease. Overall, it is essential to highlight that the significant benefits of COVID-19 vaccination far outweigh the low risk of conditions. mRNA-based vaccine technology has emerged as a rapidly deployable vaccine candidate and a viable alternative to existing vaccines. It has a very low probability of adverse health effects, confirmed by data represented by Preferred Reporting Items for Systematic Reviews and Meta-Analyses, Vaccine Adverse Event Reporting System (VAERS), Yellow card approved under CDC, WHO.
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Affiliation(s)
- Vanshika Rustagi
- Department of Zoology, Deshbandhu College, University of Delhi, New Delhi, 110019, India
| | - Shradheya R R Gupta
- Department of Zoology, Deshbandhu College, University of Delhi, New Delhi, 110019, India
| | - Chandni Talwar
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Archana Singh
- Department of Plant Molecular Biology, University of Delhi (South Campus), New Delhi, 110021, India
| | - Zhen-Zhu Xiao
- Department of Biological Sciences, The George Washington University, Washington, D.C, 20052, USA
| | - Rahul Jamwal
- Department of Zoology, Deshbandhu College, University of Delhi, New Delhi, 110019, India
| | - Kiran Bala
- Department of Zoology, Deshbandhu College, University of Delhi, New Delhi, 110019, India
| | - Akash Kumar Bhaskar
- CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi, 110025, India
| | - Shekhar Nagar
- Department of Zoology, Deshbandhu College, University of Delhi, New Delhi, 110019, India.
| | - Indrakant K Singh
- Department of Zoology, Deshbandhu College, University of Delhi, New Delhi, 110019, India.
- Delhi School of Public Health, Institute of Eminence, University of Delhi, Delhi, 110007, India.
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Benício LFMA, Nascimento ÉCM, Martins JBL. Docking heparan sulfate-based ligands as a promising inhibitor for SARS-CoV-2. J Mol Model 2024; 31:19. [PMID: 39666205 DOI: 10.1007/s00894-024-06236-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/20/2024] [Accepted: 11/26/2024] [Indexed: 12/13/2024]
Abstract
CONTEXT Heparan sulfate (HS) linear polysaccharide glycosaminoglycan compound is linked to components from the cell surface and the extracellular matrix. HS mediates SARS-CoV-2 infection through spike protein binding to cell surface receptors and is required to bind ACE2, prompting the need for electronic structure and molecular docking evaluation of this core system to exploit this attachment in developing new derivatives. Therefore, we have studied five molecules based on HS using molecular docking and electronic structure analysis. Non-covalent interaction analysis shows hydrogen bonding and van der Waals interactions in the binding to RBD-ACE2 interface and 3CLpro. SDM3 and SDM1 molecules present the lowest gap, including solvent effect under 154.6 kcal/mol, and exhibit the most reactivity behavior in this group, potentially leading to enhanced interaction in docking studies. METHODS Heparan sulfate and four derivatives were optimized using B3LYP functional with two basis sets 6-31 + G(d,p) and def2SVP. Electronic structure was used to explore the main interactions and the reactivity of these molecules, and these optimized structures were used in the molecular docking study against 3CLpro, RBD, and ACE2.
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Affiliation(s)
- Luiz F M A Benício
- Department of Pharmacy, Faculty of Health Sciences, University of Brasília, Brasília, DF, 70910-900, Brazil
| | - Érica C M Nascimento
- Computational Chemistry Laboratory, Institute of Chemistry, University of Brasilia, Brasilia, DF, 70910-900, Brazil
| | - João B L Martins
- Department of Pharmacy, Faculty of Health Sciences, University of Brasília, Brasília, DF, 70910-900, Brazil.
- Computational Chemistry Laboratory, Institute of Chemistry, University of Brasilia, Brasilia, DF, 70910-900, Brazil.
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Ramakrishnan G, Gujjula KR, Mekala JR, Sai Sree Thanay A, Praveen T, Priyanka H, Govind G, Sesha Bhavana J, Shaik B, Varakala NR. Exploring Bioactive Compounds of Rauvolfia tetraphylla L. (RT) for 3CLprotease of SARS-CoV2: GC-MS Analysis and In-Silico Studies. Cell Biochem Biophys 2024; 82:3383-3393. [PMID: 39031250 DOI: 10.1007/s12013-024-01421-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Accepted: 07/10/2024] [Indexed: 07/22/2024]
Abstract
Studies on the bioactive phytochemicals found in traditional medicinal plants are growing. This study focuses on Rauvolfia tetraphylla L. and its unique bioactive chemical composition. Previous research has demonstrated the plant's antimicrobial properties due to this composition. In this study, however, we also aim to investigate the antiviral properties of the plant. Rauvolfia tetraphylla L. has long been used for medicinal purposes. It is primarily located in Mexico, Central America, the West Indies, and northern South America. Along with checking out its in-silico SARS-CoV-2 activity, current work also evaluates the leaf extracts qualitative phytochemical, antioxidant, and cytotoxicity properties. While several conventional procedures were employed in the bio active compounds and phytochemical study that identified multiple phytochemicals, compounds derived from plants will be the most effective substitution with unfavorable side effects. The focus of this work is on in silico analysis, which determines the experimental plants activity against SARS-CoV-2 using molecular docking and pharmacokinetic analysis. We identified 20 phytochemical compounds from the GC-MS data of the plant, out of these 12 compounds failed to meet ADMET properties and the remaining 8 compounds passed TOPKAT Ames Mutagenicity. These compounds were docked against one important protein 3CLpro (PDB ID: 7DPV) that is implicated in the development of SARS-CoV-2. Docking studies have demonstrated binding results with maximum score and three compounds showed promising results. The results of this study highlighted the potential efficacy of (E,E,E,E,E,E)-()-2,6,10,15,19,23-hexamethyltetracosa-1,6,10,14,18,22-hexaen-3-ol, α-Tocospiro A, and α-Tocopherol. Furthermore, a thorough examination of the in-silico data indicates that the leaf has the potential to be a powerful source of medication and an efficient therapy in the future.
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Affiliation(s)
- Gnanasekaran Ramakrishnan
- Department of Biotechnology, Koneru Lakshmaiah Education Foundation (Deemed to be University), Green Fields, Vaddeswram, Andhra Pradesh, 522502, India
| | - Koteswara Reddy Gujjula
- Department of Biotechnology, Koneru Lakshmaiah Education Foundation (Deemed to be University), Green Fields, Vaddeswram, Andhra Pradesh, 522502, India.
| | - Janaki Ramaiah Mekala
- Department of Biotechnology, Koneru Lakshmaiah Education Foundation (Deemed to be University), Green Fields, Vaddeswram, Andhra Pradesh, 522502, India
| | - A Sai Sree Thanay
- Department of Biotechnology, Koneru Lakshmaiah Education Foundation (Deemed to be University), Green Fields, Vaddeswram, Andhra Pradesh, 522502, India
| | - T Praveen
- Department of Biotechnology, Koneru Lakshmaiah Education Foundation (Deemed to be University), Green Fields, Vaddeswram, Andhra Pradesh, 522502, India
| | - H Priyanka
- Department of Biotechnology, Koneru Lakshmaiah Education Foundation (Deemed to be University), Green Fields, Vaddeswram, Andhra Pradesh, 522502, India
| | - Geya Govind
- Department of Biotechnology, Koneru Lakshmaiah Education Foundation (Deemed to be University), Green Fields, Vaddeswram, Andhra Pradesh, 522502, India
| | - J Sesha Bhavana
- Department of Biotechnology, Koneru Lakshmaiah Education Foundation (Deemed to be University), Green Fields, Vaddeswram, Andhra Pradesh, 522502, India
| | - Baji Shaik
- Department of Biotechnology, Koneru Lakshmaiah Education Foundation (Deemed to be University), Green Fields, Vaddeswram, Andhra Pradesh, 522502, India
| | - Nikhil Reddy Varakala
- Cell Therapy Lab, University of Maryland Medical Center (UMMC), 22 South Greene Street, Baltimore, MD, 21201, USA
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16
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Mok CC, Cheung CCL, Chan KL, Tse SM, To CH. Effect of SARS-CoV2 infection on disease flares in patients with systemic lupus erythematosus: a case-control study. Rheumatology (Oxford) 2024; 63:3390-3396. [PMID: 37947324 DOI: 10.1093/rheumatology/kead601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/06/2023] [Revised: 10/08/2023] [Accepted: 10/27/2023] [Indexed: 11/12/2023] Open
Abstract
OBJECTIVES To study the effect of SARS-CoV2 infection on flares of systemic lupus erythematosus (SLE). METHODS Patients who fulfilled the ACR/SLICC criteria for SLE and had documented COVID-19 between February and November 2022 were identified retrospectively from our hospital COVID-19 registry. SLE controls who did not have SARS-CoV2 infection were randomly matched for age, sex and the time of infection in a 2:1 ratio with those infected. The primary outcome of interest was clinical flare of SLE within 90 days of COVID-19. The rate of SLE flares (mild/moderate or severe) was compared between SARS-CoV2-infected SLE patients and controls. RESULTS Ninety-one SLE patients with COVID-19 (age 48.6 (14.0) years; 95.6% women) and 182 SLE controls (age 48.7 (13.8) years; 95.6% women) were studied. Eleven of 91 (12.1%) SARS-CoV2-infected patients had serious manifestations. One (1.1%) patient died and 7 (7.7%) developed severe complications. Within 90 days of SARS-CoV2 infection, 14 (15.4%) patients developed mild/moderate clinical SLE flares and two (2.2%) patients had severe SLE flares. The incidence of SLE flares in SARS-CoV2-infected patients was significantly higher than in those without the infection (17.6% vs 5.5%; odds ratio 3.67 [95% CI: 1.59, 8.46]; P = 0.001). The changes in anti-dsDNA and complement levels, however, were not significantly different between the two groups. Among SARS-CoV2-infected SLE patients, those with clinical SLE flares had significantly lower C3 values (P = 0.004) before the infection than those without. CONCLUSION Clinical flares within 90 days were significantly more common in SLE patients infected with SARS-CoV2 than matched non-infected SLE controls.
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Affiliation(s)
- Chi Chiu Mok
- Department of Medicine, Tuen Mun Hospital, Hong Kong SAR, China
| | - Chris Ching Lam Cheung
- Department of Medicine, Tuen Mun Hospital, Hong Kong SAR, China
- Rutonjee Hospital, Hong Kong SAR, China
| | - Kar Li Chan
- Department of Medicine, Tuen Mun Hospital, Hong Kong SAR, China
| | - Sau Mei Tse
- Department of Medicine, Tuen Mun Hospital, Hong Kong SAR, China
| | - Chi Hung To
- Department of Medicine, Tuen Mun Hospital, Hong Kong SAR, China
- Pok Oi Hospital, Hong Kong SAR, China
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Ardalan M, Cool K, Gaudreault NN, Bold D, Mannix A, Hanzlicek GA, Richt JA, Pogranichniy RM. Cattle, sheep, and goat humoral immune responses against SARS-CoV-2. Vet Anim Sci 2024; 26:100408. [PMID: 39619867 PMCID: PMC11607650 DOI: 10.1016/j.vas.2024.100408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/26/2025] Open
Abstract
Following the emergence of SARS-CoV-2 in late 2019, several species of domestic and wild animals have been found to be susceptible to SARS-CoV-2 infection through experimental inoculation and animal surveillance activities. Detection of SARS-CoV-2 specific antibodies in animals is an important surveillance tool since viral shedding in animals can only be detected for a short period of time. In this study, convenience serum samples were collected from 691 cattle, 698 sheep, and 707 goats from several regions in the United States, between 2019 and 2022. The samples were evaluated for the presence of SARS-CoV-2 specific antibodies using two commercial enzyme-linked immunosorbent assays (ELISA); one based on the inhibition of the SARS-CoV-2 receptor-binding domain (sVNT) and the other based on the nucleocapsid protein (N-ELISA) of SARS-CoV-2. Positive samples from the sVNT were additionally evaluated using a conventional virus neutralization test (VNT) employing the Wuhan-like SARS-CoV-2 USA/WA1/2020 isolate. Our results indicate that ∼1 % (6/691) of cattle, ∼2 % (13/698) of sheep, and ∼2.5 % (18/707) of goat serum samples were positive when using the sVNT, whereas ∼4 % of cattle (25/691) and sheep (27/698), and 2.5 % (18/707) of goat serum samples tested positive with the N-ELISA. None of the sVNT positive cattle, sheep, or goat serum samples had detectable neutralizing antibody activity (<1:8) against the SARS-CoV-2 USA/WA1/2020 isolate by the VNT. Our results indicate low seropositivity in cattle, sheep, and goats in the U.S., indicating the importance to continue monitoring for SARS-CoV-2 prevalence in animal species that are in close contact with humans.
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Affiliation(s)
- Mehrnaz Ardalan
- Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA
| | - Konner Cool
- Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA
| | - Natasha N. Gaudreault
- Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA
| | - Dashzeveg Bold
- Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA
| | - Anna Mannix
- Veterinary Diagnostic Laboratory, Department of Diagnostic Medicine/Pathobiology College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA
| | - Gregg A. Hanzlicek
- Veterinary Diagnostic Laboratory, Department of Diagnostic Medicine/Pathobiology College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA
- Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA
| | - Juergen A. Richt
- Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA
| | - Roman M. Pogranichniy
- Veterinary Diagnostic Laboratory, Department of Diagnostic Medicine/Pathobiology College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA
- Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA
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Gomes BBM, Ferreira NN, Garibaldi PMM, Dias CFSDL, Silva LN, Almeida MAALDS, de Moraes GR, Covas DT, Kashima S, Calado RT, Fonseca BAL, Volpe GJ, Borges MDC. Impact of SARS-CoV-2 variants on COVID-19 symptomatology and severity during five waves. Heliyon 2024; 10:e40113. [PMID: 39605810 PMCID: PMC11600076 DOI: 10.1016/j.heliyon.2024.e40113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/04/2024] [Revised: 11/01/2024] [Accepted: 11/01/2024] [Indexed: 11/29/2024] Open
Abstract
Background SARS-CoV-2 variants have distinct features of transmissibility, infectivity, and aggressiveness that may cause different clinical manifestations. A better understanding of the disease presentation and progression could help to outline more precise preventive and treatment frameworks. This study describes the differences in COVID-19 presentation and outcomes across five variant waves. Methods This prospective cohort was conducted in Serrana, São Paulo State, Brazil. Clinical and demographic data was obtained from June 2020 to December 2022 as part of an enhanced health surveillance system for COVID-19, based on increasing access to diagnostic testing for SARS-CoV-2 and patient follow-up. Individuals were assessed for COVID-19 symptoms and comorbidities. Mild cases were followed up for at least 14 days, and severe cases until discharge or death. Samples were genetically sequenced, and variant waves were determined based on global SARS-CoV-2 variant predominance (>90 % sequenced samples), being as follows: Ancestral, Delta, Gamma, Omicron BA.1, and Omicron BA.2 waves. The relationship between clinical data and disease outcomes was analyzed in each variant wave. Results Patients infected during the Delta wave were the youngest (36.1 ± 18.2 years, p < 0.001). The proportion of female patients was higher across all waves. Positivity rate, disease severity, and COVID-19-related deaths varied among them. Ageusia and anosmia were related to SARS-CoV-2 positivity during the Ancestral, Gamma, and Delta waves but not in Omicron BA.1 and Omicron BA.2 waves. Diarrhea presented a lower chance of positivity only in Omicron BA.1 and Omicron BA.2. Dyspnea was the most consistent risk factor for severity across all waves. Conclusions Although patients with COVID-19 from different SARS-CoV-2 variants shared some clinical-epidemiological characteristics, each variant presented distinguishable features related to positivity and severity. This could help to understand the dynamics of COVID-19 variants and update recommendations for clinical practice.
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Affiliation(s)
- Bruno Belmonte Martinelli Gomes
- University of São Paulo, Ribeirão Preto Medical School, Avenida Bandeirantes, 3900, Ribeirão Preto, SP, Brazil
- Clinical Research Center - S, Rua Treze de Maio, 438, Serrana, SP, Brazil
| | - Natasha Nicos Ferreira
- Clinical Research Center - S, Rua Treze de Maio, 438, Serrana, SP, Brazil
- Serrana State Hospital, Rua Nossa Senhora das Dores, 811, Serrana, SP, Brazil
| | - Pedro Manoel Marques Garibaldi
- Clinical Research Center - S, Rua Treze de Maio, 438, Serrana, SP, Brazil
- Serrana State Hospital, Rua Nossa Senhora das Dores, 811, Serrana, SP, Brazil
| | | | | | | | | | - Dimas Tadeu Covas
- University of São Paulo, Ribeirão Preto Medical School, Avenida Bandeirantes, 3900, Ribeirão Preto, SP, Brazil
| | - Simone Kashima
- Center for Cell-based Therapy, Blood Center of Ribeirão Preto, Rua Tenente Catão Roxo, 2501, Ribeirão Preto, SP, Brazil
| | - Rodrigo Tocantins Calado
- University of São Paulo, Ribeirão Preto Medical School, Avenida Bandeirantes, 3900, Ribeirão Preto, SP, Brazil
| | | | - Gustavo Jardim Volpe
- Clinical Research Center - S, Rua Treze de Maio, 438, Serrana, SP, Brazil
- Serrana State Hospital, Rua Nossa Senhora das Dores, 811, Serrana, SP, Brazil
| | - Marcos de Carvalho Borges
- University of São Paulo, Ribeirão Preto Medical School, Avenida Bandeirantes, 3900, Ribeirão Preto, SP, Brazil
- Clinical Research Center - S, Rua Treze de Maio, 438, Serrana, SP, Brazil
- Serrana State Hospital, Rua Nossa Senhora das Dores, 811, Serrana, SP, Brazil
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19
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Eker F, Duman H, Ertürk M, Karav S. The potential of lactoferrin as antiviral and immune-modulating agent in viral infectious diseases. Front Immunol 2024; 15:1402135. [PMID: 39620218 PMCID: PMC11604709 DOI: 10.3389/fimmu.2024.1402135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/16/2024] [Accepted: 10/29/2024] [Indexed: 12/11/2024] Open
Abstract
Emerging infectious diseases are caused by unpredictable viruses with the dangerous potential to trigger global pandemics. These viruses typically initiate infection by utilizing the anionic structures of host cell surface receptors to gain entry. Lactoferrin (Lf) is a multifunctional glycoprotein with multiple properties such as antiviral, anti-inflammatory and antioxidant activities. Due to its cationic structure, Lf naturally interacts with certain host cell receptors, such as heparan sulfate proteoglycans, as well as viral particles and other receptors that are targeted by viruses. Therefore, Lf may interfere with virus-host cell interactions by acting as a receptor competitor for viruses. Herein we summarize studies in which this competition was investigated with SARS-CoV-2, Zika, Dengue, Hepatitis and Influenza viruses in vitro. These studies have demonstrated not only Lf's competitive properties, but also its potential intracellular impact on host cells, such as enhancing cell survival and reducing infection efficiency by inhibiting certain viral enzymes. In addition, the immunomodulatory effect of Lf is highlighted, as it can influence the activity of specific immune cells and regulate cytokine release, thereby enhancing the host's response to viral infections. Collectively, these properties promote the potential of Lf as a promising candidate for research in viral infectious diseases.
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Affiliation(s)
- Furkan Eker
- Department of Molecular Biology and Genetics, Çanakkale Onsekiz Mart University, Çanakkale, Türkiye
| | - Hatice Duman
- Department of Molecular Biology and Genetics, Çanakkale Onsekiz Mart University, Çanakkale, Türkiye
| | | | - Sercan Karav
- Department of Molecular Biology and Genetics, Çanakkale Onsekiz Mart University, Çanakkale, Türkiye
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20
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Lv H, Shi F, Yin H, Jiao Y, Wei P. Development of a double-antibody sandwich ELISA for detection of SARS-CoV-2 variants based on nucleocapsid protein-specific antibodies. Microbiol Immunol 2024; 68:393-398. [PMID: 39287179 DOI: 10.1111/1348-0421.13173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/12/2024] [Revised: 09/03/2024] [Accepted: 09/04/2024] [Indexed: 09/19/2024]
Abstract
The COVID-19 pandemic, driven by the SARS-CoV-2 virus, has posed a severe threat to global public health. Rapid, reliable, and easy-to-use detection methods for SARS-CoV-2 variants are critical for effective epidemic prevention and control. The N protein of SARS-CoV-2 serves as an ideal target for antigen detection. In this study, we achieved soluble expression of the recombinant SARS-CoV-2 N protein using an Escherichia coli expression system and generated specific monoclonal antibodies by immunizing BALB/c mice. We successfully developed 10 monoclonal antibodies against the N protein, designated 5B7, 5F2-C11, 5E2-E8, 6C3-D8, 7C8, 9F2-E9, 12H5-D11, 13G2-C10, 14E9-F6, and 15H3-E10. Using these antibodies, we established a sandwich ELISA with 6C3-D8 as the capture antibody and 5F2-C11 as the detection antibody. The assay demonstrated a sensitivity of 0.78 ng/mL and showed no cross-reactivity with MERS-CoV, HCoV-OC43, HCoV-NL63, and HCoV-229E. Furthermore, this method successfully detected both wild-type SARS-CoV-2 and its variants, including Alpha, Beta, Delta, and Omicron. These findings indicate that our sandwich ELISA exhibits excellent sensitivity, specificity, and broad-spectrum applicability, providing a robust tool for detecting SARS-CoV-2 variants.
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Affiliation(s)
- Hai Lv
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
| | - Fengjuan Shi
- NHC Key Laboratory of Enteric Pathogenic Microbiology, Jiangsu Province Center for Disease Control and Prevention, Nanjing, China
| | - Huimin Yin
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
| | - Yongjun Jiao
- NHC Key Laboratory of Enteric Pathogenic Microbiology, Jiangsu Province Center for Disease Control and Prevention, Nanjing, China
| | - Pingmin Wei
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
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Zong K, Wei C, Li W, Ruan J, Zhang S, Li J, Liu X, Zhao X, Cao R, Yan H, Li X. Identification of novel SARS-CoV-2 3CLpro inhibitors by molecular docking, in vitro assays, molecular dynamics simulations and DFT analyses. Front Pharmacol 2024; 15:1494953. [PMID: 39539614 PMCID: PMC11557435 DOI: 10.3389/fphar.2024.1494953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/11/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
Introduction SARS-CoV-2 pandemic has presented a significant threat to global health and the economy, necessitating urgent efforts to develop effective antiviral drugs. The main protease (3CLpro) of SARS-CoV-2 is a critical target for antiviral therapy due to its essential role in viral replication. Methods In order to find new structural types of 3CLpro inhibitors to facilitate the solution to the problem of new virus resistance. Six potential pharmacologically bioactive compounds were identified by utilizing structure-based virtual screening and in vitro assays from the Topscience database containing 10 million compounds. Results and Discussion Among these, compounds 34 and 36 exhibited potent inhibitory activity with IC50 values of 6.12 ± 0.42 μM and 4.47 ± 0.39 μM, respectively. To elucidate their binding mechanisms with 3CLpro, all-atom molecular dynamics (MD) simulations were conducted. Principal component analysis (PCA), free energy landscapes (FEL) and dynamic cross-correlation maps (DCCM) revealed that the binding of compounds 34 and 36 to 3CLpro significantly enhanced the structural stability of 3CLpro, reducing conformational flexibility and internal motions. The results of protein-ligand interaction showed that compounds 34 and 36 formed strong and stable interactions to key residues at active site of 3CLpro with different binding modes from S-217622. And HOMO-LUMO gap and molecular electrostatic potential distribution revealed the quantum chemical properties of compounds 34 and 36. These findings suggested that compounds 34 and 36 can be as novel SARS-CoV-2 3CLpro inhibitors and promising lead-like drug candidates for developing COVID-19 treatments.
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Affiliation(s)
- Keli Zong
- College of Chemistry and Life Science, Beijing University of Technology, Beijing, China
- Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Chaochun Wei
- College of Chemistry and Life Science, Beijing University of Technology, Beijing, China
| | - Wei Li
- Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Jiajun Ruan
- Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Susu Zhang
- Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Jingjing Li
- College of Chemistry and Life Science, Beijing University of Technology, Beijing, China
| | - Xiaojing Liu
- Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Xu Zhao
- Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Ruiyuan Cao
- Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Hong Yan
- College of Chemistry and Life Science, Beijing University of Technology, Beijing, China
| | - Xingzhou Li
- Beijing Institute of Pharmacology and Toxicology, Beijing, China
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22
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Cossu C, Franceschi V, Di Lorenzo A, Bolli E, Minesso S, Cotti C, Conti L, Donofrio G. Cross-Reactive Immune Response of Bovine Coronavirus Spike Glycoprotein to SARS-CoV-2 Variants of Concern. Int J Mol Sci 2024; 25:11509. [PMID: 39519062 PMCID: PMC11546235 DOI: 10.3390/ijms252111509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/27/2024] [Revised: 10/23/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024] Open
Abstract
The high variability observed in the clinical symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections has been attributed to the presence, in a proportion of infection-naive subjects, of pre-existing cross-reactive immune responses. Here, we demonstrate that the bovine coronavirus spike protein (BoS) may represent a source of protective immunity to SARS-CoV-2. Indeed, vaccination of BALB/c mice with a Bovine herpesvirus 4 (BoHV-4)-based vector expressing BoS induced both cell-mediated and humoral immune responses that cross-react with SARS-CoV-2 spike protein. Although the spike-specific antibodies induced by BoS did not neutralize SARS-CoV-2, the T lymphocytes activated by BoS were able to induce cytotoxicity of cells expressing spike proteins derived from several SARS-CoV-2 variants. These results demonstrate that immunization with BoS may represent a source of cross-reactive immunity to SARS-CoV-2, and that these cross-reactive immune responses may exert protective functions. These results contribute to deciphering the mechanisms responsible for lack or mildness of symptoms observed in many individuals upon SARS-CoV-2 infection and may open new ways for the development of new vaccines for coronaviruses.
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Affiliation(s)
- Chiara Cossu
- Molecular Biotechnology Center “Guido Tarone”, Department of Molecular Biotechnology and Health Sciences, University of Turin, Piazza Nizza 44, 10126 Turino, Italy; (C.C.); (A.D.L.); (E.B.)
| | - Valentina Franceschi
- Department of Veterinary Science, University of Parma, 43126 Parma, Italy; (V.F.); (S.M.); (C.C.)
| | - Antonino Di Lorenzo
- Molecular Biotechnology Center “Guido Tarone”, Department of Molecular Biotechnology and Health Sciences, University of Turin, Piazza Nizza 44, 10126 Turino, Italy; (C.C.); (A.D.L.); (E.B.)
| | - Elisabetta Bolli
- Molecular Biotechnology Center “Guido Tarone”, Department of Molecular Biotechnology and Health Sciences, University of Turin, Piazza Nizza 44, 10126 Turino, Italy; (C.C.); (A.D.L.); (E.B.)
| | - Sergio Minesso
- Department of Veterinary Science, University of Parma, 43126 Parma, Italy; (V.F.); (S.M.); (C.C.)
| | - Camilla Cotti
- Department of Veterinary Science, University of Parma, 43126 Parma, Italy; (V.F.); (S.M.); (C.C.)
| | - Laura Conti
- Molecular Biotechnology Center “Guido Tarone”, Department of Molecular Biotechnology and Health Sciences, University of Turin, Piazza Nizza 44, 10126 Turino, Italy; (C.C.); (A.D.L.); (E.B.)
| | - Gaetano Donofrio
- Department of Veterinary Science, University of Parma, 43126 Parma, Italy; (V.F.); (S.M.); (C.C.)
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23
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Nazir F, John Kombe Kombe A, Khalid Z, Bibi S, Zhang H, Wu S, Jin T. SARS-CoV-2 replication and drug discovery. Mol Cell Probes 2024; 77:101973. [PMID: 39025272 DOI: 10.1016/j.mcp.2024.101973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/11/2024] [Revised: 07/14/2024] [Accepted: 07/15/2024] [Indexed: 07/20/2024]
Abstract
The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed millions of people and continues to wreak havoc across the globe. This sudden and deadly pandemic emphasizes the necessity for anti-viral drug development that can be rapidly administered to reduce morbidity, mortality, and virus propagation. Thus, lacking efficient anti-COVID-19 treatment, and especially given the lengthy drug development process as well as the critical death tool that has been associated with SARS-CoV-2 since its outbreak, drug repurposing (or repositioning) constitutes so far, the ideal and ready-to-go best approach in mitigating viral spread, containing the infection, and reducing the COVID-19-associated death rate. Indeed, based on the molecular similarity approach of SARS-CoV-2 with previous coronaviruses (CoVs), repurposed drugs have been reported to hamper SARS-CoV-2 replication. Therefore, understanding the inhibition mechanisms of viral replication by repurposed anti-viral drugs and chemicals known to block CoV and SARS-CoV-2 multiplication is crucial, and it opens the way for particular treatment options and COVID-19 therapeutics. In this review, we highlighted molecular basics underlying drug-repurposing strategies against SARS-CoV-2. Notably, we discussed inhibition mechanisms of viral replication, involving and including inhibition of SARS-CoV-2 proteases (3C-like protease, 3CLpro or Papain-like protease, PLpro) by protease inhibitors such as Carmofur, Ebselen, and GRL017, polymerases (RNA-dependent RNA-polymerase, RdRp) by drugs like Suramin, Remdesivir, or Favipiravir, and proteins/peptides inhibiting virus-cell fusion and host cell replication pathways, such as Disulfiram, GC376, and Molnupiravir. When applicable, comparisons with SARS-CoV inhibitors approved for clinical use were made to provide further insights to understand molecular basics in inhibiting SARS-CoV-2 replication and draw conclusions for future drug discovery research.
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Affiliation(s)
- Farah Nazir
- Center of Disease Immunity and Investigation, College of Medicine, Lishui University, Lishui, 323000, China
| | - Arnaud John Kombe Kombe
- Laboratory of Structural Immunology, Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
| | - Zunera Khalid
- Laboratory of Structural Immunology, Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
| | - Shaheen Bibi
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, University of Science and Technology of China, Anhui, China
| | - Hongliang Zhang
- Center of Disease Immunity and Investigation, College of Medicine, Lishui University, Lishui, 323000, China
| | - Songquan Wu
- Center of Disease Immunity and Investigation, College of Medicine, Lishui University, Lishui, 323000, China.
| | - Tengchuan Jin
- Center of Disease Immunity and Investigation, College of Medicine, Lishui University, Lishui, 323000, China; Laboratory of Structural Immunology, Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China; Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, University of Science and Technology of China, Anhui, China; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, Anhui, China; Biomedical Sciences and Health Laboratory of Anhui Province, University of Science & Technology of China, Hefei, 230027, China; Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, 230001, China.
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24
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Cong Y, Dixit S, Perry DL, Huzella LM, Kollins E, Byrum R, Anthony SM, Drawbaugh D, Lembirik S, Postnikova E, Eaton B, Murphy M, Kocher G, Hadley K, Marketon AE, Bernbaum RM, Hischak AMW, Hart R, Vaughan N, Wada J, Qin J, St Claire MC, Schmaljohn CS, Holbrook MR. Characterization of therapeutic antibody efficacy against multiple SARS-CoV-2 variants in the hamster model. Antiviral Res 2024; 230:105987. [PMID: 39147143 PMCID: PMC11421207 DOI: 10.1016/j.antiviral.2024.105987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/28/2024] [Revised: 07/19/2024] [Accepted: 08/10/2024] [Indexed: 08/17/2024]
Abstract
The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and onset of the coronavirus disease-19 (COVID-19) pandemic led to an immediate need for therapeutic treatment options. Therapeutic antibodies were developed to fill a gap when traditional antivirals were not available. In late 2020, the United States Government undertook an effort to compare candidate therapeutic antibodies in virus neutralization assays and in the hamster model of SARS-CoV-2 infection. With the emergence of SARS-CoV-2 variants, the effort expanded to evaluate the efficacy of nearly 50 products against major variants. A subset of products was further evaluated for therapeutic efficacy in hamsters. Here we report results of the hamster studies, including pathogenicity with multiple variants, neutralization capacity of products, and efficacy testing of products against Delta and Omicron variants. These studies demonstrate the loss of efficacy of early products with variant emergence and support the use of the hamster model for evaluating therapeutics.
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Affiliation(s)
- Yu Cong
- Integrated Research Facility at Fort Detrick, Division of Clinical Research (DCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Ft. Detrick, Frederick, MD, 21702, USA
| | - Saurabh Dixit
- Integrated Research Facility at Fort Detrick, Division of Clinical Research (DCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Ft. Detrick, Frederick, MD, 21702, USA
| | - Donna L Perry
- Integrated Research Facility at Fort Detrick, Division of Clinical Research (DCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Ft. Detrick, Frederick, MD, 21702, USA
| | - Louis M Huzella
- Integrated Research Facility at Fort Detrick, Division of Clinical Research (DCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Ft. Detrick, Frederick, MD, 21702, USA
| | - Erin Kollins
- Integrated Research Facility at Fort Detrick, Division of Clinical Research (DCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Ft. Detrick, Frederick, MD, 21702, USA
| | - Russell Byrum
- Integrated Research Facility at Fort Detrick, Division of Clinical Research (DCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Ft. Detrick, Frederick, MD, 21702, USA
| | - Scott M Anthony
- Integrated Research Facility at Fort Detrick, Division of Clinical Research (DCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Ft. Detrick, Frederick, MD, 21702, USA
| | - David Drawbaugh
- Integrated Research Facility at Fort Detrick, Division of Clinical Research (DCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Ft. Detrick, Frederick, MD, 21702, USA
| | - Sanae Lembirik
- Integrated Research Facility at Fort Detrick, Division of Clinical Research (DCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Ft. Detrick, Frederick, MD, 21702, USA
| | - Elena Postnikova
- Integrated Research Facility at Fort Detrick, Division of Clinical Research (DCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Ft. Detrick, Frederick, MD, 21702, USA
| | - Brett Eaton
- Integrated Research Facility at Fort Detrick, Division of Clinical Research (DCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Ft. Detrick, Frederick, MD, 21702, USA
| | - Michael Murphy
- Integrated Research Facility at Fort Detrick, Division of Clinical Research (DCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Ft. Detrick, Frederick, MD, 21702, USA
| | - Gregory Kocher
- Integrated Research Facility at Fort Detrick, Division of Clinical Research (DCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Ft. Detrick, Frederick, MD, 21702, USA
| | - Kyra Hadley
- Integrated Research Facility at Fort Detrick, Division of Clinical Research (DCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Ft. Detrick, Frederick, MD, 21702, USA
| | - Anthony E Marketon
- Integrated Research Facility at Fort Detrick, Division of Clinical Research (DCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Ft. Detrick, Frederick, MD, 21702, USA
| | - Rebecca M Bernbaum
- Integrated Research Facility at Fort Detrick, Division of Clinical Research (DCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Ft. Detrick, Frederick, MD, 21702, USA
| | - Amanda M W Hischak
- Integrated Research Facility at Fort Detrick, Division of Clinical Research (DCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Ft. Detrick, Frederick, MD, 21702, USA
| | - Randy Hart
- Integrated Research Facility at Fort Detrick, Division of Clinical Research (DCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Ft. Detrick, Frederick, MD, 21702, USA
| | - Nick Vaughan
- Integrated Research Facility at Fort Detrick, Division of Clinical Research (DCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Ft. Detrick, Frederick, MD, 21702, USA
| | - Jiro Wada
- Integrated Research Facility at Fort Detrick, Division of Clinical Research (DCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Ft. Detrick, Frederick, MD, 21702, USA
| | - Jing Qin
- Biostatistics Research Branch (BRB), Division of Clinical Research (DCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, 20892, USA
| | - Marisa C St Claire
- Integrated Research Facility at Fort Detrick, Division of Clinical Research (DCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Ft. Detrick, Frederick, MD, 21702, USA
| | - Connie S Schmaljohn
- Integrated Research Facility at Fort Detrick, Division of Clinical Research (DCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Ft. Detrick, Frederick, MD, 21702, USA
| | - Michael R Holbrook
- Integrated Research Facility at Fort Detrick, Division of Clinical Research (DCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Ft. Detrick, Frederick, MD, 21702, USA.
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25
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Orosa Vázquez I, Díaz M, Zúñiga Rosales Y, Amada K, Chang J, Relova Hernández E, Tundidor Y, Roblejo Balbuena H, Monzón G, Torres Rives B, Noa Romero E, Carrillo Valdés D, Valdivia Álvarez I, Delahanty Fernández A, Díaz C, Solozabal J, Gil M, Sánchez B, Rojas G, Marcheco B, Carmenate T. Studying the Humoral Response against SARS-CoV-2 in Cuban COVID-19 Recovered Patients. J Immunol Res 2024; 2024:7112940. [PMID: 39359695 PMCID: PMC11446615 DOI: 10.1155/2024/7112940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/29/2024] [Revised: 07/30/2024] [Accepted: 09/05/2024] [Indexed: 10/04/2024] Open
Abstract
Understanding the immune response generated by SARS-CoV-2 is critical for assessing efficient therapeutic protocols and gaining insights into the durability of protective immunity. The current work was aimed at studying the specific humoral responses against SARS-CoV-2 in Cuban COVID-19 convalescents. We developed suitable tools and methods based on ELISA methodology, for supporting this evaluation. Here, we describe the development of an ELISA for the quantification of anti-RBD IgG titers in a large number of samples and a similar test in the presence of NH4SCN as chaotropic agent for estimating the RBD specific antibody avidity. Additionally, a simple and rapid ELISA based on antibody-mediated blockage of the binding RBD-ACE2 was implemented for detecting, as a surrogate of conventional test, the levels of anti-RBD inhibitory antibodies in convalescent sera. In a cohort of 273 unvaccinated convalescents, we identified higher anti-RBD IgG titer (1 : 1,330, p < 0.0001) and higher levels of inhibitory antibodies blocking RBD-ACE2 binding (1 : 216, p < 0.05) among those who had recovered from severe illness. Our results suggest that disease severity, and not demographic features such as age, sex, and skin color, is the main determinant of the magnitude and neutralizing ability of the anti-RBD antibody response. An additional paired longitudinal assessment in 14 symptomatic convalescents revealed a decline in the antiviral antibody response and the persistence of neutralizing antibodies for at least 4 months after the onset of symptoms. Overall, SARS-CoV-2 infection elicits different levels of antibody response according to disease severity that declines over time and can be monitored using our homemade serological assays.
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Affiliation(s)
- Ivette Orosa Vázquez
- Center of Molecular Immunology, 15th Avenue and 216 Street, Siboney, Playa, Havana, Cuba
| | - Marianniz Díaz
- Center of Molecular Immunology, 15th Avenue and 216 Street, Siboney, Playa, Havana, Cuba
| | - Yaima Zúñiga Rosales
- National Center of Medical Genetics, 31st Avenue, N°3102 and 146 Street, Cubanacán, Playa, Havana, Cuba
| | - Klayris Amada
- Julio Trigo Hospital, km 7½ Calzada de Bejucal, Diez de Octubre, Havana, Cuba
| | - Janoi Chang
- Center of Molecular Immunology, 15th Avenue and 216 Street, Siboney, Playa, Havana, Cuba
| | | | - Yaima Tundidor
- Center of Molecular Immunology, 15th Avenue and 216 Street, Siboney, Playa, Havana, Cuba
| | - Hilda Roblejo Balbuena
- National Center of Medical Genetics, 31st Avenue, N°3102 and 146 Street, Cubanacán, Playa, Havana, Cuba
| | - Giselle Monzón
- National Center of Medical Genetics, 31st Avenue, N°3102 and 146 Street, Cubanacán, Playa, Havana, Cuba
| | - Bárbara Torres Rives
- National Center of Medical Genetics, 31st Avenue, N°3102 and 146 Street, Cubanacán, Playa, Havana, Cuba
| | - Enrique Noa Romero
- Research Center of Civil Defense, José de las Lajas, San, Mayabeque, Cuba
| | | | | | | | - Claudia Díaz
- Center of Molecular Immunology, 15th Avenue and 216 Street, Siboney, Playa, Havana, Cuba
| | - Joaquín Solozabal
- Center of Molecular Immunology, 15th Avenue and 216 Street, Siboney, Playa, Havana, Cuba
| | - Mileidys Gil
- Julio Trigo Hospital, km 7½ Calzada de Bejucal, Diez de Octubre, Havana, Cuba
| | - Belinda Sánchez
- Center of Molecular Immunology, 15th Avenue and 216 Street, Siboney, Playa, Havana, Cuba
| | - Gertrudis Rojas
- Center of Molecular Immunology, 15th Avenue and 216 Street, Siboney, Playa, Havana, Cuba
| | - Beatriz Marcheco
- National Center of Medical Genetics, 31st Avenue, N°3102 and 146 Street, Cubanacán, Playa, Havana, Cuba
| | - Tania Carmenate
- Center of Molecular Immunology, 15th Avenue and 216 Street, Siboney, Playa, Havana, Cuba
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26
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Panda K, Alagarasu K, Tagore R, Paingankar M, Kumar S, Jeengar MK, Cherian S, Parashar D. RNAi-Induced Gene Silencing against Chikungunya and COVID-19: What Have We Learned So Far, and What Is the Way Forward? Viruses 2024; 16:1489. [PMID: 39339965 PMCID: PMC11437507 DOI: 10.3390/v16091489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/19/2024] [Revised: 08/27/2024] [Accepted: 08/29/2024] [Indexed: 09/30/2024] Open
Abstract
RNA interference (RNAi) is a process in which small RNA molecules (such as small interfering RNAs or siRNAs) bind to specific messenger RNAs (mRNAs), leading to its degradation and inhibition of protein synthesis. Our studies have shown that RNAi can effectively silence genes involved in the replication of the Chikungunya virus (CHIKV) in cells. However, these investigations were performed only in laboratory settings and have yet to be tested in human clinical trials. Researchers need to conduct more research to determine the safety and efficacy of RNAi-based therapies as a therapeutic agent to treat viral infections. In this review, the history of evolution of siRNA as an inhibitor of protein synthesis, along with its current developments, is discussed based on our experience. Moreover, this review examines the hurdles and future implications associated with siRNA based therapeutic approaches.
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Affiliation(s)
- Kingshuk Panda
- Dengue & Chikungunya Group, ICMR-National Institute of Virology, 20-A, Dr. Ambedkar Road, Pune 411001, India; (K.P.); (K.A.); (R.T.); (M.P.); (S.K.); (M.K.J.)
| | - Kalichamy Alagarasu
- Dengue & Chikungunya Group, ICMR-National Institute of Virology, 20-A, Dr. Ambedkar Road, Pune 411001, India; (K.P.); (K.A.); (R.T.); (M.P.); (S.K.); (M.K.J.)
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India;
| | - Rajarshee Tagore
- Dengue & Chikungunya Group, ICMR-National Institute of Virology, 20-A, Dr. Ambedkar Road, Pune 411001, India; (K.P.); (K.A.); (R.T.); (M.P.); (S.K.); (M.K.J.)
| | - Mandar Paingankar
- Dengue & Chikungunya Group, ICMR-National Institute of Virology, 20-A, Dr. Ambedkar Road, Pune 411001, India; (K.P.); (K.A.); (R.T.); (M.P.); (S.K.); (M.K.J.)
| | - Satyendra Kumar
- Dengue & Chikungunya Group, ICMR-National Institute of Virology, 20-A, Dr. Ambedkar Road, Pune 411001, India; (K.P.); (K.A.); (R.T.); (M.P.); (S.K.); (M.K.J.)
| | - Manish Kumar Jeengar
- Dengue & Chikungunya Group, ICMR-National Institute of Virology, 20-A, Dr. Ambedkar Road, Pune 411001, India; (K.P.); (K.A.); (R.T.); (M.P.); (S.K.); (M.K.J.)
| | - Sarah Cherian
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India;
- Bioinformatics Group, ICMR-National Institute of Virology, 20-A, Dr. Ambedkar Road, Pune 411001, India
| | - Deepti Parashar
- Dengue & Chikungunya Group, ICMR-National Institute of Virology, 20-A, Dr. Ambedkar Road, Pune 411001, India; (K.P.); (K.A.); (R.T.); (M.P.); (S.K.); (M.K.J.)
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India;
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27
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Eisenreich W, Leberfing J, Rudel T, Heesemann J, Goebel W. Interactions of SARS-CoV-2 with Human Target Cells-A Metabolic View. Int J Mol Sci 2024; 25:9977. [PMID: 39337465 PMCID: PMC11432161 DOI: 10.3390/ijms25189977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/15/2024] [Revised: 09/13/2024] [Accepted: 09/13/2024] [Indexed: 09/30/2024] Open
Abstract
Viruses are obligate intracellular parasites, and they exploit the cellular pathways and resources of their respective host cells to survive and successfully multiply. The strategies of viruses concerning how to take advantage of the metabolic capabilities of host cells for their own replication can vary considerably. The most common metabolic alterations triggered by viruses affect the central carbon metabolism of infected host cells, in particular glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle. The upregulation of these processes is aimed to increase the supply of nucleotides, amino acids, and lipids since these metabolic products are crucial for efficient viral proliferation. In detail, however, this manipulation may affect multiple sites and regulatory mechanisms of host-cell metabolism, depending not only on the specific viruses but also on the type of infected host cells. In this review, we report metabolic situations and reprogramming in different human host cells, tissues, and organs that are favorable for acute and persistent SARS-CoV-2 infection. This knowledge may be fundamental for the development of host-directed therapies.
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Affiliation(s)
- Wolfgang Eisenreich
- Structural Membrane Biochemistry, Bavarian NMR Center (BNMRZ), Department of Bioscience, TUM School of Natural Sciences, Technical University of Munich, Lichtenbergstr. 4, 85747 Garching, Germany;
| | - Julian Leberfing
- Structural Membrane Biochemistry, Bavarian NMR Center (BNMRZ), Department of Bioscience, TUM School of Natural Sciences, Technical University of Munich, Lichtenbergstr. 4, 85747 Garching, Germany;
| | - Thomas Rudel
- Chair of Microbiology, Biocenter, University of Würzburg, 97074 Würzburg, Germany;
| | - Jürgen Heesemann
- Max von Pettenkofer Institute, Ludwig Maximilian University of Munich, 80336 München, Germany; (J.H.); (W.G.)
| | - Werner Goebel
- Max von Pettenkofer Institute, Ludwig Maximilian University of Munich, 80336 München, Germany; (J.H.); (W.G.)
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Sharma B, Dhiman C, Hasan GM, Shamsi A, Hassan MI. Pharmacological Features and Therapeutic Implications of Plumbagin in Cancer and Metabolic Disorders: A Narrative Review. Nutrients 2024; 16:3033. [PMID: 39275349 PMCID: PMC11397539 DOI: 10.3390/nu16173033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/16/2024] [Revised: 08/30/2024] [Accepted: 09/06/2024] [Indexed: 09/16/2024] Open
Abstract
Plumbagin (PLB) is a naphthoquinone extracted from Plumbago indica. In recent times, there has been a growing body of evidence suggesting the potential importance of naphthoquinones, both natural and artificial, in the pharmacological world. Numerous studies have indicated that PLB plays a vital role in combating cancers and other disorders. There is substantial evidence indicating that PLB may have a significant role in the treatment of breast cancer, brain tumours, lung cancer, hepatocellular carcinoma, and other conditions. Moreover, its potent anti-oxidant and anti-inflammatory properties offer promising avenues for the treatment of neurodegenerative and cardiovascular diseases. A number of studies have identified various pathways that may be responsible for the therapeutic efficacy of PLB. These include cell cycle regulation, apoptotic pathways, ROS induction pathways, inflammatory pathways, and signal transduction pathways such as PI3K/AKT/mTOR, STAT3/PLK1/AKT, and others. This review aims to provide a comprehensive analysis of the diverse pharmacological roles of PLB, examining the mechanisms through which it operates and exploring its potential applications in various medical conditions. In addition, we have conducted a review of the various formulations that have been reported in the literature with the objective of enhancing the efficacy of the compound. However, the majority of the reviewed data are based on in vitro and in vivo studies. To gain a comprehensive understanding of the safety and efficacy of PLB in humans and to ascertain its potential integration into therapeutic regimens for cancer and chronic diseases, rigorous clinical trials are essential. Finally, by synthesizing current research and identifying gaps in knowledge, this review seeks to enhance our understanding of PLB and its therapeutic prospects, paving the way for future studies and clinical applications.
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Affiliation(s)
- Bhoomika Sharma
- Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Chitra Dhiman
- Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Gulam Mustafa Hasan
- Department of Basic Medical Science, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Anas Shamsi
- Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman P.O. Box 346, United Arab Emirates
| | - Md Imtiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
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Seadawy MG, Marei MI, Mohanad M, Hmed AA, Sofy AR. Genome sequencing of SARS-Co-V-2 reveals mutations including F559I and V781D in S protein and LI123-124L in the nsp6 in 21K and 21L clades. Virusdisease 2024; 35:400-419. [PMID: 39464730 PMCID: PMC11502607 DOI: 10.1007/s13337-024-00876-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/16/2024] [Accepted: 06/17/2024] [Indexed: 10/29/2024] Open
Abstract
Contagious and virulent virus variants like B.1.1.529 have complicated the 2019 global COVID-19 pandemic from Wuhan, China. Omicron, with extensive mutations and high transmissibility, is replacing Delta in some regions. Remarkably, Omicron exhibits reduced disease severity and resistance to certain vaccines and treatments. Our research sought to identify Egypt-specific variants of concern (VOCs) and their mutation patterns, aiming to provide critical insights for tailored public health strategies. We also looked at vaccine compatibility with these VOCs, as well as the efficacy of current treatments against new SARS-CoV-2 variants. We collected 103 PCR-confirmed COVID-19 cases from an Egyptian army hospital and used next-generation sequencing technology to sequence the entire viral genome. The viral genome was then assembled and reconstructed. Nextclade tools aided in clade assignment and Phylogenetic analysis, allowing classification, and understanding of these genomes' Phylogenetic relationships. Our findings reveal that the dominant VOCs in Egypt are the 21K clade, mainly Pango lineages BA.1 (34%), BA.1.1 (30.1%), and BA.1.17 (6.8%), and the 21L clade represented by Pango lineages BA.2. We also identified novel mutations, including F559I in the S protein (consistent in the 21K clade), V781D in the S protein (present in > 50% of both 21K and 21L clades), and LI123-124L in the nsp6 gene (found in both 21K and 21L clades). Finally, our research provides important insights into Egypt's evolving COVID-19 landscape, allowing for tailored responses and risk mitigation strategies for emerging variants in the region.
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Affiliation(s)
- Mohamed G. Seadawy
- Biodefense Center for Infectious and Emerging Diseases, Ministry of Defense, Cairo, Egypt
- Military Medical Academy, Cairo, Egypt
| | - Mohamed I. Marei
- Biodefense Center for Infectious and Emerging Diseases, Ministry of Defense, Cairo, Egypt
| | - Marwa Mohanad
- Biochemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October City, Egypt
| | - Ahmed A. Hmed
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo, 11884 Egypt
| | - Ahmed R. Sofy
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo, 11884 Egypt
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Lopez UM, Hasan MM, Havranek B, Islam SM. SARS-CoV-2 Resistance to Small Molecule Inhibitors. CURRENT CLINICAL MICROBIOLOGY REPORTS 2024; 11:127-139. [PMID: 39559548 PMCID: PMC11573241 DOI: 10.1007/s40588-024-00229-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Accepted: 06/05/2024] [Indexed: 11/20/2024]
Abstract
Purpose of the Review SARS-CoV-2 undergoes genetic mutations like many other viruses. Some mutations lead to the emergence of new Variants of Concern (VOCs), affecting transmissibility, illness severity, and the effectiveness of antiviral drugs. Continuous monitoring and research are crucial to comprehend variant behavior and develop effective response strategies, including identifying mutations that may affect current drug therapies. Recent Findings Antiviral therapies such as Nirmatrelvir and Ensitrelvir focus on inhibiting 3CLpro, whereas Remdesivir, Favipiravir, and Molnupiravir target nsp12, thereby reducing the viral load. However, the emergence of resistant mutations in 3CLpro and nsp12 could impact the efficiency of these small molecule drug therapeutics. Summary This manuscript summarizes mutations in 3CLpro and nsp12, which could potentially reduce the efficacy of drugs. Additionally, it encapsulates recent advancements in small molecule antivirals targeting SARS-CoV-2 viral proteins, including their potential for developing resistance against emerging variants.
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Affiliation(s)
- Uxua Modrego Lopez
- Department of Chemistry, Delaware State University, Dover, DE 19901, USA
| | - Md Mehedi Hasan
- Department of Chemistry, Delaware State University, Dover, DE 19901, USA
| | - Brandon Havranek
- Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Shahidul M Islam
- Department of Chemistry, Delaware State University, Dover, DE 19901, USA
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Malay S, Madabhavi IV, Tripathi A. SARS-CoV-2 JN.1 variant: a short review. Monaldi Arch Chest Dis 2024. [PMID: 39221683 DOI: 10.4081/monaldi.2024.2981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/08/2024] [Accepted: 07/16/2024] [Indexed: 09/04/2024] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-stranded, positive-sense RNA virus. The SARS-CoV-2 virus is evolving continuously, and many variants have been detected over the last few years. SARS-CoV-2, as an RNA virus, is more prone to mutating. The continuous evolution of the SARS-CoV-2 virus is due to genetic mutation and recombination during the genomic replication process. Recombination is a naturally occurring phenomenon in which two distinct viral lineages simultaneously infect the same cellular entity in an individual. The evolution rate depends on the rate of mutation. The rate of mutation is variable among the RNA viruses, with the SARS-CoV-2 virus exhibiting a lower rate of mutation than other RNA viruses. The novel 3'-to-5' exoribonuclease proofreading machinery is responsible for a lower rate of mutation. Infection due to the SARS-CoV-2, influenza, and respiratory syncytial virus has been reported from around the world during the same period of fall and winter, resulting in a "tripledemic." The JN.1 variant, which evolved from the predecessor, the omicron variant BA.2.86, is currently the most dominant globally. The impact of the JN.1 variant on transmissibility, disease severity, immune evasion, and diagnostic and therapeutic escape will be discussed.
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Affiliation(s)
- Sarkar Malay
- Department of Pulmonary Medicine, Indira Gandhi Medical College, Shimla, Himachal Pradesh.
| | - Irappa V Madabhavi
- Department of Medical and Pediatric Oncology, J N Medical College; KLE Academy of Higher Education and Research (KAHER), Belagavi; Kerudi Cancer Hospital, Bagalkot, Karnataka.
| | - Anurag Tripathi
- Department of Pulmonary and Critical Care Medicine, King George's Medical University, Lucknow.
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Shafique T, Javed M, Ali M, Iqbal S, Faizan M, Zidan A, Bahadur A, Mahmood S, Jaber F, Alotaibi KM, Alshalwi M. In Silico Analysis of Calotropis procera-Derived Phytochemicals Targeting 3CL Proteoase of SARS-CoV-2. Mol Biotechnol 2024:10.1007/s12033-024-01253-z. [PMID: 39177861 DOI: 10.1007/s12033-024-01253-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/17/2023] [Accepted: 07/15/2024] [Indexed: 08/24/2024]
Abstract
The coronavirus known as SARS-CoV-2 has enveloped virions with single-stranded positive-sense RNA genome. It infects mammals, including humans, via the respiratory tract. The non-structural protein of coronavirus, main protease (3CLp) is a key enzyme in the disease's progression. This study aimed to screen phytochemicals derived from Calotropis Procera as potential drugs against 3CLp. Through database search, 50 phytochemicals were identified in the Calotropis sp. To evaluate the possible drug-like properties of these phytochemicals, the studies like, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) analysis, molecular docking and density functional theory (DFT) were performed. Furthermore, GC-MS was performed using water and ethanolic extracts from the plant leaves. The ADMET analysis and docking results showed 11 phytochemicals as probable drug candidates against 3CLp of SARS-CoV-2. All these phytochemicals showed ≥ - 4.3 kcal/mol binding affinity, similar to previously reported inhibitors. Furthermore, based on band energy gap, EHOMO, ELUMO, and DFT analyses, it was shown that these phytochemicals had a significant level of reactivity necessary for the interaction. Among all, the phytochemicals uscharin, voruscharin, frugoside, coroglaucigenin, and benzoylisolineolone may be considered the top 5 drug-like candidates against 3CLp. Furthermore, the selected phytochemicals may be employed for in vitro and in vivo studies for the advancement of a probable drug alongside SARS-CoV-2.
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Affiliation(s)
- Tayyaba Shafique
- Department of Chemistry, School of Science, University of Management and Technology, Lahore, 54770, Pakistan
| | - Mohsin Javed
- Department of Chemistry, School of Science, University of Management and Technology, Lahore, 54770, Pakistan
| | - Muhammad Ali
- Department of Biochemistry, School of Sciences, University of Management and Technology, Lahore, 54770, Pakistan
| | - Shahid Iqbal
- Nottingham Ningbo China Beacons of Excellence Research and Innovation Institute, University of Nottingham Ningbo China, Ningbo, 315100, China.
| | - Muhammad Faizan
- Department of Chemical and Material Engineering, Chang Gung University, Taoyuan, Taiwan
| | - Ammar Zidan
- Biomedical Engineering Department, College of Engineering and Technologies, Al-Mustaqbal University, 51001, Babylon, Iraq
| | - Ali Bahadur
- Nanomaterials Research Center, Department of Chemistry, College of Science, Mathematics, and Technology, Wenzhou-Kean University, Wenzhou, 325060, Zhejiang Province, China.
- Dorothy and George Hennings College of Science, Mathematics and Technology, Kean University, 1000 Morris Ave, Union, NJ, 07083, USA.
| | - Sajid Mahmood
- Nottingham Ningbo China Beacons of Excellence Research and Innovation Institute, University of Nottingham Ningbo China, Ningbo, 315100, China.
- Functional Materials Group, Gulf University for Science and Technology, 32093, Mishref, Kuwait.
| | - Fadi Jaber
- Department of Biomedical Engineering, Ajman University, Ajman, UAE
- Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, UAE
| | - Khalid M Alotaibi
- Department of Chemistry, College of Science, King Saud University, PO Box 2455, 11541, Riyadh, Saudi Arabia
| | - Matar Alshalwi
- Department of Chemistry, College of Science, King Saud University, PO Box 2455, 11541, Riyadh, Saudi Arabia
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Gaiya DD, Muhammad A, Musa JS, Auta R, Dadah AJ, Bello RO, Hassan M, Eke SS, Odihi RI, Sankey M. In silico analysis of balsaminol as anti-viral agents targeting SARS-CoV-2 main protease, spike receptor binding domain and papain-like protease receptors. In Silico Pharmacol 2024; 12:75. [PMID: 39155972 PMCID: PMC11329488 DOI: 10.1007/s40203-024-00241-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/09/2023] [Accepted: 07/13/2024] [Indexed: 08/20/2024] Open
Abstract
Plant-derived phytochemicals from medicinal plants are becoming increasingly attractive natural sources of antimicrobial and antiviral agents due to their therapeutic value, mechanism of action, level of toxicity and bioavailability. The continued emergence of more immune-evasive strains and the rate of resistance to current antiviral drugs have created a need to identify new antiviral agents against SARS-CoV-2. This study investigated the antiviral potential of balsaminol, a bioactive compound from Momordica balsamina, and its inhibitory activities against SARS-CoV-2 receptor proteins. In this study, three Food and Drug Administration (FDA) COVID-19 approved drugs namely; nirmatrelvir, ritonavir and remdesivir were used as positive control. Molecular docking was performed to determine the predominant binding mode (most negative Gibbs free energy of binding/ΔG) and inhibitory activity of balsaminol against SARS-CoV-2 receptor proteins. The pharmacokinetics, toxicity, physicochemical and drug-like properties of balsaminol were evaluated to determine its potential as an active oral drug candidate as well as its non-toxicity in humans. The results show that balsaminol E has the highest binding affinity to the SARS CoV-2 papain-like protease (7CMD) with a free binding energy of - 8.7 kcal/mol, followed by balsaminol A interacting with the spike receptor binding domain (6VW1) with - 8.5 kcal/mol and balsaminol C had a binding energy of - 8.1 kcal/mol with the main protease (6LU7) comparable to the standard drugs namely ritonavir, nirmatrelvir and remdesivir. However, the ADMET and drug-like profile of balsaminol F favours it as a better potential drug candidate and inhibitor of the docked SARS-CoV-2 receptor proteins. Further preclinical studies are therefore recommended. Supplementary Information The online version contains supplementary material available at 10.1007/s40203-024-00241-0.
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Affiliation(s)
- Daniel Danladi Gaiya
- Biology Unit, Air Force Institute of Technology, Nigerian Air Force Base, P.M.B 2104, Kaduna, Nigeria
| | - Aliyu Muhammad
- Department of Biochemistry, Faculty of Life Sciences, Ahmadu Bello University, P.M.B. 1045, Samaru Zaria, Nigeria
| | - Joy Sim Musa
- Department of Chemistry, Faculty of Physical Sciences, Ahmadu Bello University, P.M.B. 1045, Samaru Zaria, Nigeria
| | - Richard Auta
- Department of Biochemistry, Faculty of Life Sciences, Kaduna State University, Tafawa Balewa Way, P.M.B. 2339, Kaduna, Nigeria
| | - Anthony John Dadah
- Department of Microbiology, Faculty of Life Sciences, Kaduna State University, Tafawa Balewa Way, P.M.B. 2339, Kaduna, Nigeria
| | | | - Madinat Hassan
- Biology Unit, Air Force Institute of Technology, Nigerian Air Force Base, P.M.B 2104, Kaduna, Nigeria
| | - Samuel Sunday Eke
- Biology Unit, Air Force Institute of Technology, Nigerian Air Force Base, P.M.B 2104, Kaduna, Nigeria
| | - Rebecca Imoo Odihi
- Department of Biological Science, Nigerian Defence Academy, Kaduna, Nigeria
| | - Musa Sankey
- Department of Chemistry, Kaduna State College of Education, Gidan Waya, Kaduna, Nigeria
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Bălăceanu-Gurău B, Dumitrascu A, Giurcăneanu C, Tatar R, Gurău CD, Orzan OA. A Comprehensive Review on the Intricate Interplay between COVID-19 Immunization and the New Onset of Pemphigus Foliaceus. Vaccines (Basel) 2024; 12:857. [PMID: 39203983 PMCID: PMC11360219 DOI: 10.3390/vaccines12080857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/09/2024] [Revised: 07/19/2024] [Accepted: 07/27/2024] [Indexed: 09/03/2024] Open
Abstract
Autoimmune bullous diseases (AIBDs) are characterized by the formation of vesicles, bullous lesions, and mucosal erosions. The autoantibodies target the cellular anchoring structures from the surface of epidermal keratinocyte named desmosomes, leading to a loss of cellular cohesion named acantholysis. AIBDs are classified into intraepidermal or subepidermal types based on clinical features, histological characteristics, and immunofluorescence patterns. Pemphigus foliaceus (PF) is an acquired, rare, autoimmune skin condition associated with autoantibodies that specifically target desmoglein-1, leading to a clinical presentation characterized by delicate cutaneous blisters, typically sparing the mucous membranes. Several factors, including genetic predisposition, environmental triggers, malignancies, medication use, and vaccination (for influenza, hepatitis B, rabies, tetanus, and more recently, severe acute respiratory syndrome Coronavirus 2 known as SARS-CoV-2), can potentially trigger the onset of pemphigus. With the advent of vaccines playing a pivotal role in combatting the 2019 coronavirus disease (COVID-19), extensive research has been conducted globally to ascertain their efficacy and potential cutaneous adverse effects. While reports of AIBDs post-COVID-19 vaccination exist in the medical literature, instances of PF following vaccination have been less commonly reported worldwide. The disease's pathophysiology is likely attributed to the resemblance between the ribonucleic acid (RNA) antigen present in these vaccines and cellular nuclear matter. The protein produced by the BNT-162b2 messenger ribonucleic acid (mRNA) vaccine includes immunogenic epitopes that could potentially trigger autoimmune phenomena in predisposed individuals through several mechanisms, including molecular mimicry, the activation of pattern recognition receptors, the polyclonal stimulation of B cells, type I interferon production, and autoinflammation. In this review, we present a comprehensive examination of the existing literature regarding the relationship between COVID-19 and PF, delving into their intricate interactions. This exploration improves the understanding of both pemphigus and mRNA vaccine mechanisms, highlighting the importance of close monitoring for PF post-immunization.
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Affiliation(s)
- Beatrice Bălăceanu-Gurău
- Department of Oncologic Dermatology, “Elias” Emergency University Hospital, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.G.); (O.A.O.)
- Clinic of Dermatology, “Elias” Emergency University Hospital, 011461 Bucharest, Romania
| | - Adrian Dumitrascu
- Division of Hospital Internal Medicine, Department of Medicine, Mayo Clinic Florida, Jacksonville, FL 32224, USA;
| | - Călin Giurcăneanu
- Department of Oncologic Dermatology, “Elias” Emergency University Hospital, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.G.); (O.A.O.)
- Clinic of Dermatology, “Elias” Emergency University Hospital, 011461 Bucharest, Romania
| | - Raluca Tatar
- Department of Plastic Reconstructive Surgery and Burns, “Grigore Alexandrescu” Clinical Emergency Hospital for Children, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Plastic Reconstructive Surgery and Burns, “Grigore Alexandrescu” Clinical Emergency Hospital for Children, 010621 Bucharest, Romania
| | - Cristian-Dorin Gurău
- Orthopedics and Traumatology Clinic, Clinical Emergency Hospital, 014451 Bucharest, Romania;
| | - Olguța Anca Orzan
- Department of Oncologic Dermatology, “Elias” Emergency University Hospital, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.G.); (O.A.O.)
- Clinic of Dermatology, “Elias” Emergency University Hospital, 011461 Bucharest, Romania
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Turbawaty DK, Sudjadi A, Lismayanti L, Rostini T, Logito V. The Performance of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Virus Using the Colorimetric Reverse-Transcription Loop Mediated Isothermal Amplification (RT-LAMP) Method in Saliva Specimens of Suspected COVID-19 Patients. Int J Gen Med 2024; 17:3329-3335. [PMID: 39081671 PMCID: PMC11288315 DOI: 10.2147/ijgm.s461613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/05/2024] [Accepted: 07/09/2024] [Indexed: 08/02/2024] Open
Abstract
Introduction Corona Virus Disease-19 (COVID-19) is a disease caused by Severe-Acute-Respiratory-Syndrome-Coronavirus-2 (SARS-CoV-2). The most reliable and widely accepted method for diagnosing this infection, despite facing various challenges, is the Reverse Transcription Polymerase Chain Reaction (RT-PCR) method, which utilizes nasopharyngeal swab sample. Reverse-transcription loop mediated isothermal amplification (RT-LAMP) is a simpler nucleic acid amplification method compared to the RT-PCR method. This method has several advantages, including: of amplification at constant temperature, faster results, and potentially greater examination capacity. Purpose This study aimed to compare the validity of the RT-LAMP method using saliva specimens with that of the RT-PCR method using nasopharyngeal smears. Methods This was an analytical observational study with a cross-sectional design. The participants were inpatients in the COVID-19 special isolation building of Hasan Sadikin General Hospital, Indonesia with a probable (clinical symptoms of covid, but not confirm NAAT examination) or confirmed diagnosis of COVID-19 from September 2021 to February 2022. The inclusion criteria are COVID-19 patients with symptoms, adult subjects, and composite mentions. Patients who were unable to secrete saliva were also excluded. Results In total, 118 specimens were collected. The validity test results of the saliva specimens using the RT-LAMP method showed sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV), of 65.5%, 100%, 100%, and 75%, respectively. The results increased in subjects treated between 3 and 7 days after symptom onset ie 73.2%, 100%, 100%, and 82.3%, respectively. Conclusion The very strong specificity accompanied by good sensitivity and NPV in the group of subjects treated 3-7 days after the onset of symptoms indicates that the RT-LAMP method using saliva specimens can be an efficient and reliable alternative tool in detecting the SARS-CoV-2 virus.
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Affiliation(s)
- Dewi Kartika Turbawaty
- Department of Clinical Pathology, Faculty of Medicine Padjadjaran University/ Dr. Hasan Sadikin General Hospital, Bandung, West Java, Indonesia
| | - Andy Sudjadi
- Department of Clinical Pathology, Faculty of Medicine Padjadjaran University/ Dr. Hasan Sadikin General Hospital, Bandung, West Java, Indonesia
| | - Leni Lismayanti
- Department of Clinical Pathology, Faculty of Medicine Padjadjaran University/ Dr. Hasan Sadikin General Hospital, Bandung, West Java, Indonesia
| | - Tiene Rostini
- Department of Clinical Pathology, Faculty of Medicine Padjadjaran University/ Dr. Hasan Sadikin General Hospital, Bandung, West Java, Indonesia
| | - Verina Logito
- Department of Clinical Pathology, Faculty of Medicine Padjadjaran University/ Dr. Hasan Sadikin General Hospital, Bandung, West Java, Indonesia
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Vidyasagar GVC, Reddy PVJ, Ghouse MM, Venkateswarulu TC, Kishor PBK, Suravajhala P, Polavarapu R. Designing and expression of novel recombinant fusion protein for efficient antigen screening of SARS-CoV-2. AMB Express 2024; 14:80. [PMID: 38990364 PMCID: PMC11239635 DOI: 10.1186/s13568-024-01719-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/02/2024] [Accepted: 05/08/2024] [Indexed: 07/12/2024] Open
Abstract
Corona virus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), claimed millions globally. After the report of the first incidence of the virus, variants emerged with each posing a unique threat than its predecessors. Though many advanced diagnostic assays like real-time PCR are available for screening of SARS-CoV-2, their applications are being hindered because of accessibility and cost. With the advent of rapid assays for antigenic screening of SARS-CoV-2 made diagnostics far easy as the assays are rapid, cost-effective and can be used at point-of-care settings. In the present study, a fusion construct was made utilising highly immunogenic B cell epitopes from the three important structural proteins of SARS-CoV-2. The protein was expressed; purified capture mAbs generated and rapid antigen assay was developed. Eight hundred and forty nasopharyngeal swab samples were screened for the evaluation of the developed assay which showed 37.14% positivity, 96.51% and 100% sensitivity and specificity respectively. The assay developed was supposed to identify SARS-CoV-2 wild-type as well as variants of concern and variants of importance in real-time conditions.
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Affiliation(s)
- G Vinaya Chandu Vidyasagar
- Genomix CARL Pvt. Ltd, YSR Kadapa, Pulivendula, 516 390, Andhra Pradesh, India
- Department of Biotechnology, Vignan's Foundation for Science, Technology & Research, Vadlamudi, Guntur, 522 213, India
| | - P V Janardhan Reddy
- Genomix CARL Pvt. Ltd, YSR Kadapa, Pulivendula, 516 390, Andhra Pradesh, India
| | - M Md Ghouse
- Genomix CARL Pvt. Ltd, YSR Kadapa, Pulivendula, 516 390, Andhra Pradesh, India
| | - T C Venkateswarulu
- Department of Biotechnology, Vignan's Foundation for Science, Technology & Research, Vadlamudi, Guntur, 522 213, India
| | - P B Kavi Kishor
- Genomix CARL Pvt. Ltd, YSR Kadapa, Pulivendula, 516 390, Andhra Pradesh, India
- Department of Genetics, Osmania University, Hyderabad, 500 007, India
| | - Prashanth Suravajhala
- Amrita School of Biotechnology, Amrita Viswa Vidyapeetham, Clappana, 690525, Kerala, India.
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Latosińska M, Latosińska JN. The Chameleon Strategy-A Recipe for Effective Ligand Screening for Viral Targets Based on Four Novel Structure-Binding Strength Indices. Viruses 2024; 16:1073. [PMID: 39066235 PMCID: PMC11281727 DOI: 10.3390/v16071073] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/14/2024] [Revised: 06/28/2024] [Accepted: 06/30/2024] [Indexed: 07/28/2024] Open
Abstract
The RNA viruses SARS-CoV, SARS-CoV-2 and MERS-CoV encode the non-structural Nsp16 (2'-O-methyltransferase) that catalyzes the transfer of a methyl group from S-adenosylmethionine (SAM) to the first ribonucleotide in mRNA. Recently, it has been found that breaking the bond between Nsp16 and SAM substrate results in the cessation of mRNA virus replication. To date, only a limited number of such inhibitors have been identified, which can be attributed to a lack of an effective "recipe". The aim of our study was to propose and verify a rapid and effective screening protocol dedicated to such purposes. We proposed four new indices describing structure-binding strength (structure-binding affinity, structure-hydrogen bonding, structure-steric and structure-protein-ligand indices) were then applied and shown to be extremely helpful in determining the degree of increase or decrease in binding affinity in response to a relatively small change in the ligand structure. After initial pre-selection, based on similarity to SAM, we limited the study to 967 compounds, so-called molecular chameleons. They were then docked in the Nsp16 protein pocket, and 10 candidate ligands were selected using the novel structure-binding affinity index. Subsequently the selected 10 candidate ligands and 8 known inhibitors and were docked to Nsp16 pockets from SARS-CoV-2, MERS-CoV and SARS-CoV. Based on the four new indices, the best ligands were selected and a new one was designed by tuning them. Finally, ADMET profiling and molecular dynamics simulations were performed for the best ligands. The new structure-binding strength indices can be successfully applied not only to screen and tune ligands, but also to determine the effectiveness of the ligand in response to changes in the target viral entity, which is particularly useful for assessing drug effectiveness in the case of alterations in viral proteins. The developed approach, the so-called chameleon strategy, has the capacity to introduce a novel universal paradigm to the field of drugs design, including RNA antivirals.
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Payen SH, Adhikari K, Petereit J, Uppal T, Rossetto CC, Verma SC. SARS-CoV-2 superinfection in CD14 + monocytes with latent human cytomegalovirus (HCMV) promotes inflammatory cascade. Virus Res 2024; 345:199375. [PMID: 38642618 PMCID: PMC11061749 DOI: 10.1016/j.virusres.2024.199375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/16/2024] [Revised: 04/07/2024] [Accepted: 04/17/2024] [Indexed: 04/22/2024]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of coronavirus disease 2019 (COVID-19), has posed significant challenges to global health. While much attention has been directed towards understanding the primary mechanisms of SARS-CoV-2 infection, emerging evidence suggests co-infections or superinfections with other viruses may contribute to increased morbidity and mortality, particularly in severe cases of COVID-19. Among viruses that have been reported in patients with SARS-CoV-2, seropositivity for Human cytomegalovirus (HCMV) is associated with increased COVID-19 risk and hospitalization. HCMV is a ubiquitous beta-herpesvirus with a seroprevalence of 60-90 % worldwide and one of the leading causes of mortality in immunocompromised individuals. The primary sites of latency for HCMV include CD14+ monocytes and CD34+ hematopoietic cells. In this study, we sought to investigate SARS-CoV-2 infection of CD14+ monocytes latently infected with HCMV. We demonstrate that CD14+ cells are susceptible and permissive to SARS-CoV-2 infection and detect subgenomic transcripts indicative of replication. To further investigate the molecular changes triggered by SARS-CoV-2 infection in HCMV-latent CD14+ monocytes, we conducted RNA sequencing coupled with bioinformatic differential gene analysis. The results revealed significant differences in cytokine-cytokine receptor interactions and inflammatory pathways in cells superinfected with replication-competent SARS-CoV-2 compared to the heat-inactivated and mock controls. Notably, there was a significant upregulation in transcripts associated with pro-inflammatory response factors and a decrease in anti-inflammatory factors. Taken together, these findings provide a basis for the heightened inflammatory response, offering potential avenues for targeted therapeutic interventions among HCMV-infected severe cases of COVID-19. SUMMARY: COVID-19 patients infected with secondary viruses have been associated with a higher prevalence of severe symptoms. Individuals seropositive for human cytomegalovirus (HCMV) infection are at an increased risk for severe COVID-19 disease and hospitalization. HCMV reactivation has been reported in severe COVID-19 cases with respiratory failure and could be the result of co-infection with SARS-CoV-2 and HCMV. In a cell culture model of superinfection, HCMV has previously been shown to increase infection of SARS-CoV-2 of epithelial cells by upregulating the human angiotensin-converting enzyme-2 (ACE2) receptor. In this study, we utilize CD14+ monocytes, a major cell type that harbors latent HCMV, to investigate co-infection of SARS-CoV-2 and HCMV. This study is a first step toward understanding the mechanism that may facilitate increased COVID-19 disease severity in patients infected with SARS-CoV-2 and HCMV.
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Affiliation(s)
- Shannon Harger Payen
- Reno School of Medicine, Department of Microbiology & Immunology/MS 320, University of Nevada, Reno, NV 89557, United States
| | - Kabita Adhikari
- Reno School of Medicine, Department of Microbiology & Immunology/MS 320, University of Nevada, Reno, NV 89557, United States
| | - Juli Petereit
- Nevada Bioinformatics Center (RRID:SCR_017802), University of Nevada, Reno, NV 89557, United States
| | - Timsy Uppal
- Reno School of Medicine, Department of Microbiology & Immunology/MS 320, University of Nevada, Reno, NV 89557, United States
| | - Cyprian C Rossetto
- Reno School of Medicine, Department of Microbiology & Immunology/MS 320, University of Nevada, Reno, NV 89557, United States
| | - Subhash C Verma
- Reno School of Medicine, Department of Microbiology & Immunology/MS 320, University of Nevada, Reno, NV 89557, United States.
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Xie S, Cao S, Wu J, Xie Z, Liu YT, Fu W, Zhao Q, Liu L, Yang L, Li J. In silico-based screening of natural products as potential inhibitors of SARS-CoV-2 macrodomain 1. J Biomol Struct Dyn 2024; 42:5229-5237. [PMID: 37349935 DOI: 10.1080/07391102.2023.2226745] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/23/2023] [Accepted: 06/09/2023] [Indexed: 06/24/2023]
Abstract
The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide has led to over 600 million cases of coronavirus disease 2019 (COVID-19). Identifying effective molecules that can counteract the virus is imperative. SARS-CoV-2 macrodomain 1 (Mac1) represents a promising antiviral drug target. In this study, we predicted potential inhibitors of SARS-CoV-2 Mac1 from natural products using in silico-based screening. Based on the high-resolution crystal structure of Mac1 bound to its endogenous ligand ADP-ribose (ADPr), we first performed a docking-based virtual screening of Mac1 inhibitors against a natural product library and obtained five representative compounds (MC1-MC5) by clustering analysis. All five compounds were stably bound to Mac1 during 500 ns long molecular dynamics simulations. The binding free energy of these compounds to Mac1 was calculated using molecular mechanics generalized Born surface area and further refined with localized volume-based metadynamics. The results demonstrated that both MC1 (-9.8 ± 0.3 kcal/mol) and MC5 (-9.6 ± 0.3 kcal/mol) displayed more favorable affinities to Mac1 with respect to ADPr (-8.9 ± 0.3 kcal/mol), highlighting their potential as potent SARS-CoV-2 Mac1 inhibitors. Overall, this study provides potential SARS-CoV-2 Mac1 inhibitors, which may pave the way for developing effective therapeutics for COVID-19.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Song Xie
- College of Chemistry, Fuzhou University, Fuzhou, China
| | - Shoujing Cao
- College of Chemistry, Fuzhou University, Fuzhou, China
| | - Juhong Wu
- College of Chemistry, Fuzhou University, Fuzhou, China
| | - Zhinuo Xie
- College of Chemistry, Fuzhou University, Fuzhou, China
| | | | - Wei Fu
- College of Chemistry, Fuzhou University, Fuzhou, China
| | - Qianqian Zhao
- College of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Lin Liu
- College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Lin Yang
- Department of Pharmacy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Jinyu Li
- College of Chemistry, Fuzhou University, Fuzhou, China
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Bicchieraro G, Ciurnelli R, Graziani A, Wong AYW, Camilloni B, Mencacci A, Spaccapelo R. SARS-CoV-2 Molecular Evolution: A Focus on Omicron Variants in Umbria, Italy. Microorganisms 2024; 12:1330. [PMID: 39065097 PMCID: PMC11279337 DOI: 10.3390/microorganisms12071330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/03/2024] [Revised: 06/21/2024] [Accepted: 06/27/2024] [Indexed: 07/28/2024] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 6 million deaths worldwide, and the spread of new variants over time increased the ability of this virus to cause infection. The Omicron variant was detected for the first time in Umbria, a region of central Italy, in November 2021 and it induced an unprecedented increase in the number of infection cases. Here, we analysed 3300 SARS-CoV-2 positive samples collected in Umbria between April 2022 and December 2023. We traced the molecular evolution of SARS-CoV-2 variants over time through the Next-Generation Sequencing (NGS) approach. We assessed correlation between SARS-CoV-2 infection and patients' health status. In total, 17.3% of our samples came from patients hospitalised as a consequence of COVID-19 infection even though 81.4% of them received at least three vaccine doses. We identified only Omicron variants, and the BA.5 lineage was detected in the majority of our samples (49.2%). Omicron variants outcompeted each other through the acquisition of mutations especially in Spike glycoprotein that are fingerprints of each variant. Viral antigenic evolution confers higher immunological escape and makes a continuous improvement of vaccine formulation necessary. The continuous update of international genomic databases with sequencing results obtained by emergent pathogens is essential to manage a possible future pandemic.
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Affiliation(s)
- Giulia Bicchieraro
- Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (G.B.); (A.G.); (A.Y.W.W.); (A.M.)
| | - Raffaella Ciurnelli
- Medical Microbiology Section, Santa Maria della Misericordia Hospital, 06132 Perugia, Italy;
| | - Alessandro Graziani
- Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (G.B.); (A.G.); (A.Y.W.W.); (A.M.)
| | - Alicia Yoke Wei Wong
- Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (G.B.); (A.G.); (A.Y.W.W.); (A.M.)
| | - Barbara Camilloni
- Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (G.B.); (A.G.); (A.Y.W.W.); (A.M.)
- Medical Microbiology Section, Santa Maria della Misericordia Hospital, 06132 Perugia, Italy;
| | - Antonella Mencacci
- Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (G.B.); (A.G.); (A.Y.W.W.); (A.M.)
- Medical Microbiology Section, Santa Maria della Misericordia Hospital, 06132 Perugia, Italy;
| | - Roberta Spaccapelo
- Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (G.B.); (A.G.); (A.Y.W.W.); (A.M.)
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Poličar PG, Špendl M, Curk T, Zupan B. Teaching bioinformatics through the analysis of SARS-CoV-2: project-based training for computer science students. Bioinformatics 2024; 40:i20-i29. [PMID: 38940150 PMCID: PMC11211835 DOI: 10.1093/bioinformatics/btae208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 06/29/2024] Open
Abstract
MOTIVATION We learn more effectively through experience and reflection than through passive reception of information. Bioinformatics offers an excellent opportunity for project-based learning. Molecular data are abundant and accessible in open repositories, and important concepts in biology can be rediscovered by reanalyzing the data. RESULTS In the manuscript, we report on five hands-on assignments we designed for master's computer science students to train them in bioinformatics for genomics. These assignments are the cornerstones of our introductory bioinformatics course and are centered around the study of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). They assume no prior knowledge of molecular biology but do require programming skills. Through these assignments, students learn about genomes and genes, discover their composition and function, relate SARS-CoV-2 to other viruses, and learn about the body's response to infection. Student evaluation of the assignments confirms their usefulness and value, their appropriate mastery-level difficulty, and their interesting and motivating storyline. AVAILABILITY AND IMPLEMENTATION The course materials are freely available on GitHub at https://github.com/IB-ULFRI.
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Affiliation(s)
- Pavlin G Poličar
- Faculty of Computer and Information Science, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia
| | - Martin Špendl
- Faculty of Computer and Information Science, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia
| | - Tomaž Curk
- Faculty of Computer and Information Science, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia
| | - Blaž Zupan
- Faculty of Computer and Information Science, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia
- Department of Education, Innovation and Technology, Baylor College of Medicine, 1 Baylor Plz, Houston, TX 77030, United States
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Khan P, Aufdembrink LM, Adamala KP, Engelhart AE. PACRAT: pathogen detection with aptamer-observed cascaded recombinase polymerase amplification-in vitro transcription. RNA (NEW YORK, N.Y.) 2024; 30:891-900. [PMID: 38637016 PMCID: PMC11182012 DOI: 10.1261/rna.079891.123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 11/15/2023] [Accepted: 04/04/2024] [Indexed: 04/20/2024]
Abstract
The SARS-CoV-2 pandemic underscored the need for early, rapid, and widespread pathogen detection tests that are readily accessible. Many existing rapid isothermal detection methods use the recombinase polymerase amplification (RPA), which exhibits polymerase chain reaction (PCR)-like sensitivity, specificity, and even higher speed. However, coupling RPA to other enzymatic reactions has proven difficult. For the first time, we demonstrate that with tuning of buffer conditions and optimization of reagent concentrations, RPA can be cascaded into an in vitro transcription reaction, enabling detection using fluorescent aptamers in a one-pot reaction. We show that this reaction, which we term PACRAT (pathogen detection with aptamer-observed cascaded recombinase polymerase amplification-in vitro transcription) can be used to detect SARS-CoV-2 RNA with single-copy detection limits, Escherichia coli with single-cell detection limits, and 10-min detection times. Further demonstrating the utility of our one-pot, cascaded amplification system, we show PACRAT can be used for multiplexed detection of the pathogens SARS-CoV-2 and E. coli, along with multiplexed detection of two variants of SARS-CoV-2.
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Affiliation(s)
- Pavana Khan
- Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota 55455, USA
| | - Lauren M Aufdembrink
- Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota 55455, USA
| | - Katarzyna P Adamala
- Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota 55455, USA
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA
| | - Aaron E Engelhart
- Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota 55455, USA
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA
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Deshmukh N, Talkal R, Lakshmi B. In silico screening of potential inhibitors from Cordyceps species against SARS-CoV-2 main protease. J Biomol Struct Dyn 2024; 42:4395-4411. [PMID: 37325819 DOI: 10.1080/07391102.2023.2225110] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/29/2022] [Accepted: 06/05/2023] [Indexed: 06/17/2023]
Abstract
Coronavirus disease 2019 (COVID-19) is a result of a retroviral infection of SARS-CoV-2. Due to its virulence and high infection rate, it is a matter of serious concern and a global health emergency. Currently available COVID-19 vaccines approved by regulatory bodies around the world have been shown to provide significant protection against COVID-19. But no vaccine is 100% effective at preventing infection, also they have varying efficacy rates and different side effects. However, the main protease (Mpro) of SARS-CoV-2 has been identified as a key drug target due to its essential role in viral infection and its minimal similarity with human proteases. Cordyceps mushrooms have been found to have various therapeutic properties that could effectively combat SARS-CoV-2, including improve lung functioning, anti-viral, immunomodulators, anti-infectious, and anti-inflammatory. The present study aims to screen and evaluate the inhibitory potential of the bioactive molecules from the Cordyceps species against the Mpro of SARS-CoV-2. The bioactive molecules were screened based on their docking score, molecular interactions in the binding pocket, ADME properties, toxicity, carcinogenicity, and mutagenicity. Among all the molecules that were tested, cordycepic acid was the most effective and promising candidate, with a binding affinity of -8.10 kcal/mol against Mpro. The molecular dynamics (MD) simulation and free binding energy calculations revealed that the cordycepic acid-Mpro complex was highly stable and showed fewer conformational fluctuations. These findings need to be investigated further through in-vitro and in-vivo studies for additional validation.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Niketan Deshmukh
- L J School of Applied Sciences, L J University, Ahmedabad, India
| | - Reshma Talkal
- Gujarat Biotechnology Research Centre, Gandhinagar, India
| | - Bhaskaran Lakshmi
- Department of Biotechnology, Kadi Sarva Vishwavidyalaya, Gandhinagar, India
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44
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Van Nam L, Dien TC, Bang LVN, Thach PN, Van Duyet L. Genetic features of SARS-CoV-2 Alpha, Delta, and Omicron variants and their association with the clinical severity of COVID-19 in Vietnam. IJID REGIONS 2024; 11:100348. [PMID: 38601946 PMCID: PMC11004080 DOI: 10.1016/j.ijregi.2024.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Academic Contribution Register] [Received: 02/18/2024] [Revised: 03/06/2024] [Accepted: 03/07/2024] [Indexed: 04/12/2024]
Abstract
Objectives We investigated the genetic variations in the Alpha, Delta, and Omicron variants of SARS-CoV-2 and their association with clinical status and treatment outcomes in patients with COVID-19. Methods MiSeq was used to sequence the Alpha, Delta, and Omicron genomes, and MEGA 6.6 was used to define the nucleotide variations. We determined the association between clinical severity and treatment outcomes for the SARS-CoV-2 variants. Results The BA.1.1 and BA.2 lineages of the Omicron variant had 57-59 mutations, which is 2-2.7-fold higher than that of the B.1.1.7 (Alpha), B.1.617.2, and AY.57 (Delta) lineages. We found distinct mutations in SARS-CoV-2: five in Alpha (C26305T, G26558T, G7042T, C14120T, and C27509T); seven in Delta (C26408T, C1403T, C5184T, C9891T, T11418C, C11514T, and C22227T); and three in Omicron (C26408T, C8991T, and C25810T). Patients with the Delta variant had a severe rate of 23.8%, a critical rate of 53.7%, and a mortality rate of 38.9%, which were significantly higher than those with the Omicron and Alpha variants. Conclusions The Alpha, Delta, and Omicron variants in this study had genetic diversity and differed from the strains reported in other countries, with the Delta variant producing significantly more clinical severity and mortality than the Alpha and Omicron variants.
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Affiliation(s)
- Le Van Nam
- Departments of Infectious Disease, Military Hospital, Hanoi, Vietnam
| | - Trinh Cong Dien
- Departments of Infectious Disease, Military Hospital, Hanoi, Vietnam
| | | | - Pham Ngoc Thach
- Micobiology and Molecular Biology Department, National Hospital for Tropical Diseases, Hanoi, Vietnam
| | - Le Van Duyet
- Micobiology and Molecular Biology Department, National Hospital for Tropical Diseases, Hanoi, Vietnam
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Samy A, Hassan A, Hegazi NM, Farid M, Elshafei M. Network pharmacology, molecular docking, and dynamics analyses to predict the antiviral activity of ginger constituents against coronavirus infection. Sci Rep 2024; 14:12059. [PMID: 38802394 PMCID: PMC11130167 DOI: 10.1038/s41598-024-60721-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/25/2023] [Accepted: 04/26/2024] [Indexed: 05/29/2024] Open
Abstract
COVID-19 is a global pandemic that caused a dramatic loss of human life worldwide, leading to accelerated research for antiviral drug discovery. Herbal medicine is one of the most commonly used alternative medicine for the prevention and treatment of many conditions including respiratory system diseases. In this study, a computational pipeline was employed, including network pharmacology, molecular docking simulations, and molecular dynamics simulations, to analyze the common phytochemicals of ginger rhizomes and identify candidate constituents as viral inhibitors. Furthermore, experimental assays were performed to analyze the volatile and non-volatile compounds of ginger and to assess the antiviral activity of ginger oil and hydroalcoholic extract. Network pharmacology analysis showed that ginger compounds target human genes that are involved in related cellular processes to the viral infection. Docking analysis highlighted five pungent compounds and zingiberenol as potential inhibitors for the main protease (Mpro), spike receptor-binding domain (RBD), and human angiotensin-converting enzyme 2 (ACE2). Then, (6)-gingerdiacetate was selected for molecular dynamics (MD) simulations as it exhibited the best binding interactions and free energies over the three target proteins. Trajectories analysis of the three complexes showed that RBD and ACE2 complexes with the ligand preserved similar patterns of root mean square deviation (RMSD) and radius of gyration (Rg) values to their respective native structures. Finally, experimental validation of the ginger hydroalcoholic extract confirmed the existence of (6)-gingerdiacetate and revealed the strong antiviral activity of the hydroalcoholic extract with IC50 of 2.727 μ g / ml . Our study provides insights into the potential antiviral activity of (6)-gingerdiacetate that may enhance the host immune response and block RBD binding to ACE2, thereby, inhibiting SARS-CoV-2 infection.
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Affiliation(s)
- Asmaa Samy
- Zewail City of Science and Technology, Giza, 12578, Egypt
| | - Afnan Hassan
- Biomedical Sciences Program, Zewail City of Science and Technology, Giza, 12578, Egypt
| | - Nesrine M Hegazi
- Department of Phytochemistry and Plant Systematics, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Cairo, 12622, Egypt
| | - Mai Farid
- Department of Phytochemistry and Plant Systematics, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Cairo, 12622, Egypt
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Khan S, Rathod P, Gupta VK, Khedekar PB, Chikhale RV. Evolution and Impact of Nucleic Acid Amplification Test (NAAT) for Diagnosis of Coronavirus Disease. Anal Chem 2024; 96:8124-8146. [PMID: 38687959 PMCID: PMC11112543 DOI: 10.1021/acs.analchem.3c05225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/18/2023] [Revised: 04/11/2024] [Accepted: 04/15/2024] [Indexed: 05/02/2024]
Affiliation(s)
- Sumbul
Fatma Khan
- Department
of Pharmaceutical Sciences, Rashtrasant
Tukadoji Maharaj Nagpur University, Nagpur 440033, MS India
| | - Priyanka Rathod
- Department
of Pharmaceutical Sciences, Rashtrasant
Tukadoji Maharaj Nagpur University, Nagpur 440033, MS India
| | - Vivek K. Gupta
- Department
of Biochemistry, National JALMA Institute
for Leprosy & Other Mycobacterial Diseases (ICMR), Agra -282004, India
| | - Pramod B. Khedekar
- Department
of Pharmaceutical Sciences, Rashtrasant
Tukadoji Maharaj Nagpur University, Nagpur 440033, MS India
| | - Rupesh V. Chikhale
- UCL
School of Pharmacy, Department of Pharmaceutical and Biological Chemistry, University College London, London WC1N 1AX, United Kingdom
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Quddusi DM, Hiremath SA, Bajcinca N. Mutation prediction in the SARS-CoV-2 genome using attention-based neural machine translation. MATHEMATICAL BIOSCIENCES AND ENGINEERING : MBE 2024; 21:5996-6018. [PMID: 38872567 DOI: 10.3934/mbe.2024264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 06/15/2024]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) has been evolving rapidly after causing havoc worldwide in 2020. Since then, it has been very hard to contain the virus owing to its frequently mutating nature. Changes in its genome lead to viral evolution, rendering it more resistant to existing vaccines and drugs. Predicting viral mutations beforehand will help in gearing up against more infectious and virulent versions of the virus in turn decreasing the damage caused by them. In this paper, we have proposed different NMT (neural machine translation) architectures based on RNNs (recurrent neural networks) to predict mutations in the SARS-CoV-2-selected non-structural proteins (NSP), i.e., NSP1, NSP3, NSP5, NSP8, NSP9, NSP13, and NSP15. First, we created and pre-processed the pairs of sequences from two languages using k-means clustering and nearest neighbors for training a neural translation machine. We also provided insights for training NMTs on long biological sequences. In addition, we evaluated and benchmarked our models to demonstrate their efficiency and reliability.
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Affiliation(s)
- Darrak Moin Quddusi
- Chair of Mechatronics in the Faculty of Mechanical and Process Engineering, Rheinland-Pfalz Technical University of Kaiserslautern-Landau, Kaiserslautern 67663, Germany
| | - Sandesh Athni Hiremath
- Chair of Mechatronics in the Faculty of Mechanical and Process Engineering, Rheinland-Pfalz Technical University of Kaiserslautern-Landau, Kaiserslautern 67663, Germany
| | - Naim Bajcinca
- Chair of Mechatronics in the Faculty of Mechanical and Process Engineering, Rheinland-Pfalz Technical University of Kaiserslautern-Landau, Kaiserslautern 67663, Germany
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Morales M, Yang MY, Goddard WA, Gray HB, Winkler JR. Copper(II) coordination to the intrinsically disordered region of SARS-CoV-2 Nsp1. Proc Natl Acad Sci U S A 2024; 121:e2402653121. [PMID: 38722808 PMCID: PMC11098128 DOI: 10.1073/pnas.2402653121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/06/2024] [Accepted: 04/04/2024] [Indexed: 05/18/2024] Open
Abstract
The intrinsically disordered C-terminal peptide region of severe acute respiratory syndrome coronavirus 2 nonstructural protein-1 (Nsp1-CT) inhibits host protein synthesis by blocking messenger RNA (mRNA) access to the 40S ribosome entrance tunnel. Aqueous copper(II) ions bind to the disordered peptide with micromolar affinity, creating a possible strategy to restore protein synthesis during host infection. Electron paramagnetic resonance (EPR) and tryptophan fluorescence measurements on a 10-residue model of the disordered protein region (Nsp1-CT10), combined with advanced quantum mechanics calculations, suggest that the peptide binds to copper(II) as a multidentate ligand. Two optimized computational models of the copper(II)-peptide complexes were derived: One corresponding to pH 6.5 and the other describing the complex at pH 7.5 to 8.5. Simulated EPR spectra based on the calculated model structures are in good agreement with experimental spectra.
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Affiliation(s)
- Maryann Morales
- Beckman Institute, California Institute of Technology, Pasadena, CA91125
| | - Moon Young Yang
- Beckman Institute, California Institute of Technology, Pasadena, CA91125
| | - William A. Goddard
- Beckman Institute, California Institute of Technology, Pasadena, CA91125
| | - Harry B. Gray
- Beckman Institute, California Institute of Technology, Pasadena, CA91125
| | - Jay R. Winkler
- Beckman Institute, California Institute of Technology, Pasadena, CA91125
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Zhao Z, Bashiri S, Ziora ZM, Toth I, Skwarczynski M. COVID-19 Variants and Vaccine Development. Viruses 2024; 16:757. [PMID: 38793638 PMCID: PMC11125726 DOI: 10.3390/v16050757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/22/2024] [Revised: 05/08/2024] [Accepted: 05/08/2024] [Indexed: 05/26/2024] Open
Abstract
Coronavirus disease 2019 (COVID-19), the global pandemic caused by severe acute respiratory syndrome 2 virus (SARS-CoV-2) infection, has caused millions of infections and fatalities worldwide. Extensive SARS-CoV-2 research has been conducted to develop therapeutic drugs and prophylactic vaccines, and even though some drugs have been approved to treat SARS-CoV-2 infection, treatment efficacy remains limited. Therefore, preventive vaccination has been implemented on a global scale and represents the primary approach to combat the COVID-19 pandemic. Approved vaccines vary in composition, although vaccine design has been based on either the key viral structural (spike) protein or viral components carrying this protein. Therefore, mutations of the virus, particularly mutations in the S protein, severely compromise the effectiveness of current vaccines and the ability to control COVID-19 infection. This review begins by describing the SARS-CoV-2 viral composition, the mechanism of infection, the role of angiotensin-converting enzyme 2, the host defence responses against infection and the most common vaccine designs. Next, this review summarizes the common mutations of SARS-CoV-2 and how these mutations change viral properties, confer immune escape and influence vaccine efficacy. Finally, this review discusses global strategies that have been employed to mitigate the decreases in vaccine efficacy encountered against new variants.
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Affiliation(s)
- Ziyao Zhao
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia; (Z.Z.); (S.B.); (I.T.)
| | - Sahra Bashiri
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia; (Z.Z.); (S.B.); (I.T.)
| | - Zyta M. Ziora
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia;
| | - Istvan Toth
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia; (Z.Z.); (S.B.); (I.T.)
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia;
- School of Pharmacy, The University of Queensland, Woolloongabba, QLD 4102, Australia
| | - Mariusz Skwarczynski
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia; (Z.Z.); (S.B.); (I.T.)
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50
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Yadav AJ, Kumar S, Maurya S, Bhagat K, Padhi AK. Interface design of SARS-CoV-2 symmetrical nsp7 dimer and machine learning-guided nsp7 sequence prediction reveals physicochemical properties and hotspots for nsp7 stability, adaptation, and therapeutic design. Phys Chem Chem Phys 2024; 26:14046-14061. [PMID: 38686454 DOI: 10.1039/d4cp01014k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 05/02/2024]
Abstract
The COVID-19 pandemic, driven by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates a profound understanding of the virus and its lifecycle. As an RNA virus with high mutation rates, SARS-CoV-2 exhibits genetic variability leading to the emergence of variants with potential implications. Among its key proteins, the RNA-dependent RNA polymerase (RdRp) is pivotal for viral replication. Notably, RdRp forms dimers via non-structural protein (nsp) subunits, particularly nsp7, crucial for efficient viral RNA copying. Similar to the main protease (Mpro) of SARS-CoV-2, there is a possibility that the nsp7 might also undergo mutational selection events to generate more stable and adaptable versions of nsp7 dimer during virus evolution. However, efforts to obtain such cohesive and comprehensive information are lacking. To address this, we performed this study focused on deciphering the molecular intricacies of nsp7 dimerization using a multifaceted approach. Leveraging computational protein design (CPD), machine learning (ML), AlphaFold v2.0-based structural analysis, and several related computational approaches, we aimed to identify critical residues and mutations influencing nsp7 dimer stability and adaptation. Our methodology involved identifying potential hotspot residues within the dimeric nsp7 interface using an interface-based CPD approach. Through Rosetta-based symmetrical protein design, we designed and modulated nsp7 dimerization, considering selected interface residues. Analysis of physicochemical features revealed acceptable structural changes and several structural and residue-specific insights emphasizing the intricate nature of such protein-protein complexes. Our ML models, particularly the random forest regressor (RFR), accurately predicted binding affinities and ML-guided sequence predictions corroborated CPD findings, elucidating potential nsp7 mutations and their impact on binding affinity. Validation against clinical sequencing data demonstrated the predictive accuracy of our approach. Moreover, AlphaFold v2.0 structural analyses validated optimal dimeric configurations of affinity-enhancing designs, affirming methodological precision. Affinity-enhancing designs exhibited favourable energetics and higher binding affinity as compared to their counterparts. The obtained physicochemical properties, molecular interactions, and sequence predictions advance our understanding of SARS-CoV-2 evolution and inform potential avenues for therapeutic intervention against COVID-19.
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Affiliation(s)
- Amar Jeet Yadav
- Laboratory for Computational Biology & Biomolecular Design, School of Biochemical Engineering, Indian Institute of Technology (BHU), Varanasi 221005, Uttar Pradesh, India.
| | - Shivank Kumar
- Laboratory for Computational Biology & Biomolecular Design, School of Biochemical Engineering, Indian Institute of Technology (BHU), Varanasi 221005, Uttar Pradesh, India.
| | - Shweata Maurya
- Laboratory for Computational Biology & Biomolecular Design, School of Biochemical Engineering, Indian Institute of Technology (BHU), Varanasi 221005, Uttar Pradesh, India.
| | - Khushboo Bhagat
- Laboratory for Computational Biology & Biomolecular Design, School of Biochemical Engineering, Indian Institute of Technology (BHU), Varanasi 221005, Uttar Pradesh, India.
| | - Aditya K Padhi
- Laboratory for Computational Biology & Biomolecular Design, School of Biochemical Engineering, Indian Institute of Technology (BHU), Varanasi 221005, Uttar Pradesh, India.
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