1
|
Jung J, Sung JS, Kwon S, Bae HE, Kang MJ, Jose J, Lee M, Pyun JC. Transmembrane protease serine 2 (TMPRSS2) inhibitors screened from an Fv-antibody library for preventing SARS-CoV-2 infection. RSC Med Chem 2025:d4md00992d. [PMID: 39990164 PMCID: PMC11843257 DOI: 10.1039/d4md00992d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/17/2024] [Accepted: 02/11/2025] [Indexed: 02/25/2025] Open
Abstract
Fv-antibodies targeting the transmembrane protease serine 2 (TMPRSS2) were screened from an Fv-antibody library for inhibiting SARS-CoV-2 infection. Fv-antibodies were derived from the variable region of heavy-chain immunoglobulin G (IgG), which consisted of three complementarity-determining regions (CDRs) and frame regions (FRs). The Fv-antibody library was prepared through site-directed mutagenesis of CDR3 region. The proteolytic cleavage site (S2' site) of TMPRSS2 on the spike protein (SP) of SARS-CoV-2 was used as a screening probe for the library. Two Fv-antibodies were screened and subsequently expressed as soluble recombinant proteins. The binding affinities of the expressed Fv-antibodies were estimated using a surface plasmon resonance (SPR) biosensor. The two expressed Fv-antibodies specifically bound to the active site of TMPRSS2 which interacts with S2' site in the proprotein convertase (PPC) region. The neutralizing activities of the two expressed Fv-antibodies were demonstrated using a cell-based infection assay with pseudo-viruses that expressed the SP of four types of SARS-CoV-2 variants: Wu-1 (D614), Delta (B.1.617.2), Omicron (BA.2), and Omicron (BA.4/5). Additionally, a docking simulation was performed to analyze the interaction between the screened Fv-antibodies and the active sites of TMPRSS2.
Collapse
Affiliation(s)
- Jaeyong Jung
- Department of Materials Science and Engineering, Yonsei University 50 Yonsei-ro Seodaemun-gu Seoul 03722 Korea
| | - Jeong Soo Sung
- Department of Materials Science and Engineering, Yonsei University 50 Yonsei-ro Seodaemun-gu Seoul 03722 Korea
| | - Soonil Kwon
- Department of Materials Science and Engineering, Yonsei University 50 Yonsei-ro Seodaemun-gu Seoul 03722 Korea
| | - Hyung Eun Bae
- Department of Materials Science and Engineering, Yonsei University 50 Yonsei-ro Seodaemun-gu Seoul 03722 Korea
| | - Min-Jung Kang
- Korea Institute of Science and Technology (KIST) Seoul 02456 Korea
| | - Joachim Jose
- Institute of Pharmaceutical and Medical Chemistry, Westfälischen Wilhelms-Universität Münster Muenster Germany
| | - Misu Lee
- Division of Life Sciences, College of Life Science and Bioengineering, Incheon National University Incheon 22012 Korea
- Institute for New Drug Development, College of Life Science and Bioengineering, Incheon National University Incheon 22012 Korea
| | - Jae-Chul Pyun
- Department of Materials Science and Engineering, Yonsei University 50 Yonsei-ro Seodaemun-gu Seoul 03722 Korea
| |
Collapse
|
2
|
Coish JM, MacNeil LA, MacNeil AJ. The SARS-CoV-2 antibody-dependent enhancement façade. Microbes Infect 2024:105464. [PMID: 39662700 DOI: 10.1016/j.micinf.2024.105464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/02/2024] [Revised: 12/05/2024] [Accepted: 12/06/2024] [Indexed: 12/13/2024]
Abstract
Antibody-dependent enhancement (ADE) is an immunological paradox whereby sensitization following a primary viral infection results in the subsequent enhancement of a similar secondary infection. This idiosyncratic immune response has been established in dengue virus infections, driven by four antigenically related serotypes co-circulating in endemic regions. Several coronaviruses exhibit antibody-mediated mechanisms of viral entry, which has led to speculation of an ADE capacity for SARS-CoV-2, though in vivo and epidemiological evidence do not currently support this phenomenon. Three distinct antibody-dependent mechanisms for SARS-CoV-2 entry have recently been demonstrated: 1. FcR-dependent, 2. ACE2-FcR-interdependent, and 3. FcR-independent. These mechanisms of viral entry may be dependent on SARS-CoV-2 antibody specificity; antibodies targeting the receptor binding domain (RBD) typically result in Fc-dependent and ACE2-FcR-interdependent entry, whereas antibodies targeting the N-terminal domain can induce a conformational change to the RBD that optimizes ACE2-receptor binding domain interactions independent of Fc receptors. Whether these antibody-dependent entry mechanisms of SARS-CoV-2 result in the generation of infectious progenies and enhancement of infection has not been robustly demonstrated. Furthermore, ADE of SARS-CoV-2 mediated by antigenic seniority remains a theoretical concern, as no evidence suggests that SARS-CoV-2 imprinting blunts a subsequent immune response, contributing to severe COVID-19 disease.
Collapse
Affiliation(s)
- Jeremia M Coish
- Department of Health Sciences, Brock University, St. Catharines, Ontario, L2S 3A1, Canada
| | - Lori A MacNeil
- Department of Biological Sciences, Brock University, St. Catharines, Ontario, L2S 3A1, Canada
| | - Adam J MacNeil
- Department of Health Sciences, Brock University, St. Catharines, Ontario, L2S 3A1, Canada.
| |
Collapse
|
3
|
Oduro-Kwateng E, Soliman ME. DON/DRP-104 as potent serine protease inhibitors implicated in SARS-CoV-2 infection: Comparative binding modes with human TMPRSS2 and novel therapeutic approach. J Cell Biochem 2024; 125:e30528. [PMID: 38284235 DOI: 10.1002/jcb.30528] [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: 12/03/2023] [Revised: 12/31/2023] [Accepted: 01/10/2024] [Indexed: 01/30/2024]
Abstract
Human transmembrane serine protease 2 (TMPRSS2) is an important member of the type 2 transmembrane serine protease (TTSP) family with significant therapeutic markings. The search for potent TMPRSS2 inhibitors against severe acute respiratory syndrome coronavirus 2 infection with favorable tissue specificity and off-site toxicity profiles remains limited. Therefore, probing the anti-TMPRSS2 potential of enhanced drug delivery systems, such as nanotechnology and prodrug systems, has become compelling. We report the first in silico study of TMPRSS2 against a prodrug, [isopropyl(S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate] also known as DRP-104 synthesized from 6-Diazo-5-oxo-l-norleucine (DON). We performed comparative studies on DON and DRP-104 against a clinically potent TMPRSS2 inhibitor, nafamostat, and a standard serine protease inhibitor, 4-(2-Aminoethyl) benzenesulfonyl fluoride (AEBSF) against TMPRSS2 and found improved TMPRSS2 inhibition through synergistic binding of the S1/S1' subdomains. Both DON and DRP-104 had better thermodynamic profiles than AEBSF and nafamostat. DON was found to confer structural stability with strong positive correlated inter-residue motions, whereas DRP-104 was found to confer kinetic stability with restricted residue displacements and reduced loop flexibility. Interestingly, the Scavenger Receptor Cysteine-Rich (SRCR) domain of TMPRSS2 may be involved in its inhibition mechanics. Two previously unidentified loops, designated X (270-275) and Y (293-296) underwent minimal and major structural transitions, respectively. In addition, residues 273-277 consistently transitioned to a turn conformation in all ligated systems, whereas unique transitions were identified for other transitioning residue groups in each TMPRSS2-inhibitor complex. Intriguingly, while both DON and DRP-104 showed similar loop transition patterns, DRP-104 preserved loop structural integrity. As evident from our systematic comparative study using experimentally/clinically validated inhibitors, DRP-104 may serve as a potent and novel TMPRSS2 inhibitor and warrants further clinical investigation.
Collapse
Affiliation(s)
- Ernest Oduro-Kwateng
- School of Health Sciences, Molecular Bio-Computation and Drug Design Research Group, Westville Campus, University of KwaZulu Natal, Durban, South Africa
| | - Mahmoud E Soliman
- School of Health Sciences, Molecular Bio-Computation and Drug Design Research Group, Westville Campus, University of KwaZulu Natal, Durban, South Africa
| |
Collapse
|
4
|
Kundrapu DB, Chaitanya AK, Manaswi K, Kumari S, Malla R. Quercetin and taxifolin inhibits TMPRSS2 activity and its interaction with EGFR in paclitaxel-resistant breast cancer cells: An in silico and in vitro study. Chem Biol Drug Des 2024; 104:e14600. [PMID: 39075030 DOI: 10.1111/cbdd.14600] [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: 02/27/2024] [Revised: 07/11/2024] [Accepted: 07/16/2024] [Indexed: 07/31/2024]
Abstract
Transmembrane protease/serine (TMPRSS2), a type II transmembrane serine protease, plays a crucial role in different stages of cancer. Recent studies have reported that the triggering epidermal growth factor receptor (EGFR) activation through protease action promotes metastasis. However, there are no reports on the interaction of TMPRSS2 with EGFR, especially in triple-negative triple negative (TNBC). The current study investigates the unexplored interaction between TMPRSS2 and EGFR, which are key partners mediating metastasis. This interaction is explored for potential targeting using quercetin (QUE) and taxifolin (TAX). TMPRSS2 expression patterns in breast cancer (BC) tissues and subtypes have been predicted, with the prognostic significance assessed using the GENT2.0 database. Validation of TMPRSS2 expression was performed in normal and TNBC tissues, including drug-resistant cell lines, utilizing GEO datasets. TMPRSS2 was further validated as a predictive biomarker for FDA-approved chemotherapeutics through transcriptomic data from BC patients. The study demonstrated the association of TMPRSS2 with EGFR through in silico analysis and validates the findings in TNBC cohorts using the TIMER2.0 web server and the TCGA dataset through C-Bioportal. Molecular docking and molecular dynamic simulation studies identified QUE and TAX as best leads targeting TMPRSS2. They inhibited cell-free TMPRSS2 activity like clinical inhibitor of TMPRSS2, Camostat mesylate. In cell-based assays focused on paclitaxel-resistant TNBC (TNBC/PR), QUE and TAX demonstrated potent inhibitory activity against extracellular and membrane-bound TMPRSS2, with low IC50 values. Furthermore, ELISA and cell-based AlphaLISA assays demonstrated that QUE and TAX inhibit the interaction of TMPRSS2 with EGFR. Additionally, QUE and TAX exhibited significant inhibition of proliferation and cell cycle accompanied by notable alterations in the morphology of TNBC/PR cells. This study provides valuable insights into potential of QUE and TAX targeting TMPRSS2 overexpressing TNBC.
Collapse
Affiliation(s)
- Durga Bhavani Kundrapu
- Cancer Biology, Department of Life Sciences, GITAM School of Science, GITAM (Deemed to be University), Visakhapatnam, Andhra Pradesh, India
- Department of Life Sciences, GITAM School of Science, GITAM (Deemed to be University), Visakhapatnam, Andhra Pradesh, India
| | - Amajala Krishna Chaitanya
- Department of Life Sciences, GITAM School of Science, GITAM (Deemed to be University), Visakhapatnam, Andhra Pradesh, India
| | - Kothapalli Manaswi
- Department of Life Sciences, GITAM School of Science, GITAM (Deemed to be University), Visakhapatnam, Andhra Pradesh, India
| | - Seema Kumari
- Cancer Biology, Department of Life Sciences, GITAM School of Science, GITAM (Deemed to be University), Visakhapatnam, Andhra Pradesh, India
- Department of Life Sciences, GITAM School of Science, GITAM (Deemed to be University), Visakhapatnam, Andhra Pradesh, India
| | - RamaRao Malla
- Cancer Biology, Department of Life Sciences, GITAM School of Science, GITAM (Deemed to be University), Visakhapatnam, Andhra Pradesh, India
- Department of Life Sciences, GITAM School of Science, GITAM (Deemed to be University), Visakhapatnam, Andhra Pradesh, India
| |
Collapse
|
5
|
Alkhofash NF, Ali BR. The Evaluation of Drugs as Potential Modulators of the Trafficking and Maturation of ACE2, the SARS-CoV-2 Receptor. Biomolecules 2024; 14:764. [PMID: 39062478 PMCID: PMC11274373 DOI: 10.3390/biom14070764] [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: 05/18/2024] [Revised: 06/15/2024] [Accepted: 06/17/2024] [Indexed: 07/28/2024] Open
Abstract
ACE2, part of the angiotensin-converting enzyme family and the renin-angiotensin-aldosterone system (RAAS), plays vital roles in cardiovascular and renal functions. It is also the primary receptor for SARS-CoV-2, enabling its entry into cells. This project aimed to study ACE2's cellular trafficking and maturation to the cell surface and assess the impact of various drugs and compounds on these processes. We used cellular and biochemical analyses to evaluate these compounds as potential leads for COVID-19 therapeutics. Our screening assay focused on ACE2 maturation levels and subcellular localization with and without drug treatments. Results showed that ACE2 maturation is generally fast and robust, with certain drugs having a mild impact. Out of twenty-three tested compounds, eight significantly reduced ACE2 maturation levels, and three caused approximately 20% decreases. Screening trafficking inhibitors revealed significant effects from most molecular modulators of protein trafficking, mild effects from most proposed COVID-19 drugs, and no effects from statins. This study noted that manipulating ACE2 levels could be beneficial or harmful, depending on the context. Thus, using this approach to uncover leads for COVID-19 therapeutics requires a thorough understanding ACE2's biogenesis and biology.
Collapse
Affiliation(s)
- Nesreen F. Alkhofash
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain P.O. Box 15551, United Arab Emirates;
| | - Bassam R. Ali
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain P.O. Box 15551, United Arab Emirates;
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al-Ain P.O. Box 15551, United Arab Emirates
| |
Collapse
|
6
|
Ullah S, Ullah A, Waqas M, Halim SA, Pasha AR, Shafiq Z, Mali SN, Jawarkar RD, Khan A, Khalid A, Abdalla AN, Kashtoh H, Al-Harrasi A. Structural, dynamic behaviour, in-vitro and computational investigations of Schiff's bases of 1,3-diphenyl urea derivatives against SARS-CoV-2 spike protein. Sci Rep 2024; 14:12588. [PMID: 38822113 PMCID: PMC11143201 DOI: 10.1038/s41598-024-63345-9] [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: 12/15/2023] [Accepted: 05/28/2024] [Indexed: 06/02/2024] Open
Abstract
The COVID-19 has had a significant influence on people's lives across the world. The viral genome has undergone numerous unanticipated changes that have given rise to new varieties, raising alarm on a global scale. Bioactive phytochemicals derived from nature and synthetic sources possess lot of potential as pathogenic virus inhibitors. The goal of the recent study is to report new inhibitors of Schiff bases of 1,3-dipheny urea derivatives against SARS COV-2 spike protein through in-vitro and in-silico approach. Total 14 compounds were evaluated, surprisingly, all the compounds showed strong inhibition with inhibitory values between 79.60% and 96.00% inhibition. Here, compounds 3a (96.00%), 3d (89.60%), 3e (84.30%), 3f (86.20%), 3g (88.30%), 3h (86.80%), 3k (82.10%), 3l (90.10%), 3m (93.49%), 3n (85.64%), and 3o (81.79%) exhibited high inhibitory potential against SARS COV-2 spike protein. While 3c also showed significant inhibitory potential with 79.60% inhibition. The molecular docking of these compounds revealed excellent fitting of molecules in the spike protein receptor binding domain (RBD) with good interactions with the key residues of RBD and docking scores ranging from - 4.73 to - 5.60 kcal/mol. Furthermore, molecular dynamics simulation for 150 ns indicated a strong stability of a complex 3a:6MOJ. These findings obtained from the in-vitro and in-silico study reflect higher potency of the Schiff bases of 1,3-diphenyl urea derivatives. Furthermore, also highlight their medicinal importance for the treatment of SARS COV-2 infection. Therefore, these small molecules could be a possible drug candidate.
Collapse
Affiliation(s)
- Saeed Ullah
- Natural and Medical Sciences Research Center, University of Nizwa, Birkat-ul-Mouz 616, Nizwa, Sultanate of Oman
| | - Atta Ullah
- Natural and Medical Sciences Research Center, University of Nizwa, Birkat-ul-Mouz 616, Nizwa, Sultanate of Oman
| | - Muhammad Waqas
- Natural and Medical Sciences Research Center, University of Nizwa, Birkat-ul-Mouz 616, Nizwa, Sultanate of Oman
| | - Sobia Ahsan Halim
- Natural and Medical Sciences Research Center, University of Nizwa, Birkat-ul-Mouz 616, Nizwa, Sultanate of Oman
| | - Anam Rubbab Pasha
- Natural and Medical Sciences Research Center, University of Nizwa, Birkat-ul-Mouz 616, Nizwa, Sultanate of Oman
- Institute of Chemical Sciences, Bahauddin Zakariya University, Multan, 60800, Pakistan
| | - Zahid Shafiq
- Institute of Chemical Sciences, Bahauddin Zakariya University, Multan, 60800, Pakistan.
| | - Suraj N Mali
- School of Pharmacy, D.Y. Patil University (Deemed to be University), Sector 7, Nerul, Navi Mumbai, 400706, India
| | - Rahul D Jawarkar
- Department of Medicinal Chemistry and Drug Discovery, Dr. Rajendra Gode Institute of Pharmacy, University Mardi Road, Amravati, 444603, India
| | - Ajmal Khan
- Natural and Medical Sciences Research Center, University of Nizwa, Birkat-ul-Mouz 616, Nizwa, Sultanate of Oman.
| | - Asaad Khalid
- Substance Abuse and Toxicology Research Center, Jazan University, P.O. Box: 114, 45142, Jazan, Saudi Arabia
| | - Ashraf N Abdalla
- Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, 21955, Makkah, Saudi Arabia
| | - Hamdy Kashtoh
- Department of Biotechnology, Yeungnam University, Gyeongsan, 38541, Gyeongbuk, Republic of Korea.
| | - Ahmed Al-Harrasi
- Natural and Medical Sciences Research Center, University of Nizwa, Birkat-ul-Mouz 616, Nizwa, Sultanate of Oman.
| |
Collapse
|
7
|
Li X, Li X, Kang B, Eom Y, Lee HK, Kim DH, Zhong J, Song JS. Effects of particulate matter exposure on the expression of the SARS-CoV-2 ACE2 receptor in ocular surface tissues and cells. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2024; 31:8768-8780. [PMID: 38180673 DOI: 10.1007/s11356-023-31607-0] [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: 10/04/2023] [Accepted: 12/14/2023] [Indexed: 01/06/2024]
Abstract
Particulate matter (PM) has been reported to be one of the risk factor for COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, although the ocular surface is deeply affected by both PM exposure and SARS-COV-2 infection, no studies have investigated the effects of PM exposure on the ocular route of SARS-COV-2 infection. To this end, we explored the effects of PM on the expression of SARS-COV-2-associated receptors and proteins in ocular surface. Herein, short- and long-term PM-exposed rat models were established by topically administering PM for 3 and 10 days, respectively. Immortalized human corneal epithelial cells (HCECs) and human conjunctival epithelial cells (HCjECs) were exposed to PM. ACE2, TMPRSS2, CD147, and ADAM17 expression levels were measured by western blot analysis. Our results show that short-term PM exposure had little effect on the expressions of ACE2, TMPRSS2, and CD147 in ocular surface tissues. However, long-term PM exposure decreased the ACE2 expression in conjunctival tissues and increased the CD147 expression in corneal or conjunctival tissues. PM exposure reduced the ACE2 expression by increasing the ADAM17 expression and ACE2 shedding level in HCECs and HCjECs. Our findings suggest that long-term PM exposure down-regulate the expression of the SARS-CoV-2 receptor ACE2 in conjunctival tissues through ADAM17-dependent ACE2 shedding. However, long-term PM exposure up-regulates the expression of another SARS-CoV-2 receptor CD147 in ocular surface tissues, accompanied by ocular surface damage and cytotoxicity. This study provides a new insight into uncovering potential risk factors for infection with SARS-CoV-2 via the ocular route.
Collapse
Affiliation(s)
- Xiangzhe Li
- Department of Ophthalmology, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Xuemin Li
- Department of Ophthalmology, Korea University College of Medicine, 80, Guro-Dong, Guro-Gu, Seoul, 152-703, South Korea
| | - Boram Kang
- Department of Ophthalmology, Korea University College of Medicine, 80, Guro-Dong, Guro-Gu, Seoul, 152-703, South Korea
| | - Youngsub Eom
- Department of Ophthalmology, Korea University College of Medicine, 80, Guro-Dong, Guro-Gu, Seoul, 152-703, South Korea
| | - Hyung Keun Lee
- Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, South Korea
| | - Dong Hyun Kim
- Department of Ophthalmology, Korea University College of Medicine, 80, Guro-Dong, Guro-Gu, Seoul, 152-703, South Korea
| | - Jingxiang Zhong
- Department of Ophthalmology, The Sixth Affiliated Hospital of Jinan University, Dongguan, China
- Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Jong Suk Song
- Department of Ophthalmology, Korea University College of Medicine, 80, Guro-Dong, Guro-Gu, Seoul, 152-703, South Korea.
| |
Collapse
|
8
|
Khalifa HO, Al Ramahi YM. After the Hurricane: Anti-COVID-19 Drugs Development, Molecular Mechanisms of Action and Future Perspectives. Int J Mol Sci 2024; 25:739. [PMID: 38255813 PMCID: PMC10815681 DOI: 10.3390/ijms25020739] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/03/2023] [Revised: 12/22/2023] [Accepted: 12/26/2023] [Indexed: 01/24/2024] Open
Abstract
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a new coronavirus in the Coronaviridae family. The COVID-19 pandemic, caused by SARS-CoV-2, has undoubtedly been the largest crisis of the twenty-first century, resulting in over 6.8 million deaths and 686 million confirmed cases, creating a global public health issue. Hundreds of notable articles have been published since the onset of this pandemic to justify the cause of viral spread, viable preventive measures, and future therapeutic approaches. As a result, this review was developed to provide a summary of the current anti-COVID-19 drugs, as well as their timeline, molecular mode of action, and efficacy. It also sheds light on potential future treatment options. Several medications, notably hydroxychloroquine and lopinavir/ritonavir, were initially claimed to be effective in the treatment of SARS-CoV-2 but eventually demonstrated inadequate activity, and the Food and Drug Administration (FDA) withdrew hydroxychloroquine. Clinical trials and investigations, on the other hand, have demonstrated the efficacy of remdesivir, convalescent plasma, and monoclonal antibodies, 6-Thioguanine, hepatitis C protease inhibitors, and molnupiravir. Other therapeutics, including inhaled medicines, flavonoids, and aptamers, could pave the way for the creation of novel anti-COVID-19 therapies. As future pandemics are unavoidable, this article urges immediate action and extensive research efforts to develop potent specialized anti-COVID-19 medications.
Collapse
Affiliation(s)
- Hazim O. Khalifa
- Department of Veterinary Medicine, College of Agriculture and Veterinary Medicine, United Arab Emirates University, Al Ain P.O. Box 1555, United Arab Emirates;
- Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - Yousef M. Al Ramahi
- Department of Veterinary Medicine, College of Agriculture and Veterinary Medicine, United Arab Emirates University, Al Ain P.O. Box 1555, United Arab Emirates;
| |
Collapse
|
9
|
Singh S, Agrawal N, Goyal A. Unraveling Amentoflavone's Therapeutic Potential in Alzheimer's Disease: A Preclinical Assessment. Comb Chem High Throughput Screen 2024; 27:1851-1860. [PMID: 38441013 DOI: 10.2174/0113862073301291240229102657] [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: 02/15/2024] [Accepted: 02/16/2024] [Indexed: 03/06/2024]
Abstract
Alzheimer's disease is one of the neurodegenerative diseases which causes cognition deficit. There are currently few medications available to treat Alzheimer's disease, even though researchers have devoted a great deal of time studying the condition and offering many benefits. Thus, only a few drugs are available for the treatment of Alzheimer's disease. Amentoflavone is a dietary component found in many plants and herbs that has several health advantages. Amentoflavone has demonstrated strong protective benefits against a range of brain illnesses in preclinical trials, most frequently in Alzheimer's disease. Amentoflavone, a biflavonoid, can be identified in a variety of herbs upon isolation. Considering the beneficial properties of this compound, this review emphasizes the pharmacological effects and botanical sources of amentoflavone, as well as the compound's benefits and possible applications in the treatment of Alzheimer's disorders.
Collapse
Affiliation(s)
- Sushma Singh
- Institute of Pharmaceutical Research, GLA University, Mathura, 281406, U.P., India
- Department of Pharmacology, Shri Ramswaroop Memorial University Village-Hadauri, Post-Tindola, Lucknow-Deva Road, Barabanki, U.P., 225003, India
| | - Neetu Agrawal
- Institute of Pharmaceutical Research, GLA University, Mathura, 281406, U.P., India
| | - Ahsas Goyal
- Institute of Pharmaceutical Research, GLA University, Mathura, 281406, U.P., India
| |
Collapse
|
10
|
Le K, Kannappan S, Kim T, Lee JH, Lee HR, Kim KK. Structural understanding of SARS-CoV-2 virus entry to host cells. Front Mol Biosci 2023; 10:1288686. [PMID: 38033388 PMCID: PMC10683510 DOI: 10.3389/fmolb.2023.1288686] [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: 09/04/2023] [Accepted: 10/16/2023] [Indexed: 12/02/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major global health concern associated with millions of fatalities worldwide. Mutant variants of the virus have further exacerbated COVID-19 mortality and infection rates, emphasizing the urgent need for effective preventive strategies. Understanding the viral infection mechanism is crucial for developing therapeutics and vaccines. The entry of SARS-CoV-2 into host cells is a key step in the infection pathway and has been targeted for drug development. Despite numerous reviews of COVID-19 and the virus, there is a lack of comprehensive reviews focusing on the structural aspects of viral entry. In this review, we analyze structural changes in Spike proteins during the entry process, dividing the entry process into prebinding, receptor binding, proteolytic cleavage, and membrane fusion steps. By understanding the atomic-scale details of viral entry, we can better target the entry step for intervention strategies. We also examine the impacts of mutations in Spike proteins, including the Omicron variant, on viral entry. Structural information provides insights into the effects of mutations and can guide the development of therapeutics and vaccines. Finally, we discuss available structure-based approaches for the development of therapeutics and vaccines. Overall, this review provides a detailed analysis of the structural aspects of SARS-CoV-2 viral entry, highlighting its significance in the development of therapeutics and vaccines against COVID-19. Therefore, our review emphasizes the importance of structural information in combating SARS-CoV-2 infection.
Collapse
Affiliation(s)
- Kim Le
- Department of Precision Medicine, Sungkyunkwan University School of Medicine, Institute of Antibacterial Resistance Research and Therapeutics, Sungkyunkwan University, Suwon, Republic of Korea
| | - Shrute Kannappan
- Department of Precision Medicine, Sungkyunkwan University School of Medicine, Institute of Antibacterial Resistance Research and Therapeutics, Sungkyunkwan University, Suwon, Republic of Korea
- Research Center for Advanced Materials Technology Core Research Institute, Suwon, Republic of Korea
| | - Truc Kim
- Department of Precision Medicine, Sungkyunkwan University School of Medicine, Institute of Antibacterial Resistance Research and Therapeutics, Sungkyunkwan University, Suwon, Republic of Korea
| | - Jung Heon Lee
- Research Center for Advanced Materials Technology Core Research Institute, Suwon, Republic of Korea
- School of Advanced Materials and Science Engineering, Sungkyunkwan University, Suwon, Republic of Korea
| | - Hye-Ra Lee
- Department of Biotechnology and Bioinformatics, College of Science and Technology, Korea University, Sejong, Republic of Korea
| | - Kyeong Kyu Kim
- Department of Precision Medicine, Sungkyunkwan University School of Medicine, Institute of Antibacterial Resistance Research and Therapeutics, Sungkyunkwan University, Suwon, Republic of Korea
| |
Collapse
|
11
|
Rizka Nurcahyaningtyas H, Irene A, Tri Wibowo J, Yunovilsa Putra M, Yanuar A. Identification of potential Indonesian marine invertebrate bioactive compounds as TMPRSS2 and SARS-CoV-2 Omicron spike protein inhibitors through computational screening. ARAB J CHEM 2023; 16:104984. [PMID: 37234226 PMCID: PMC10186851 DOI: 10.1016/j.arabjc.2023.104984] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/11/2023] [Accepted: 05/08/2023] [Indexed: 05/27/2023] Open
Abstract
The coronavirus pandemic led to the announcement of a worldwide health emergency. The SARS-CoV-2 Omicron variant, which swiftly spread worldwide, has fueled existing challenges. Appropriate medication is necessary to avoid severe SARS-CoV-2 disease. The human TMPRSS2 and SARS-CoV-2 Omicron spike protein, which are required for viral entry into the host phase, were identified as the target proteins through computational screening. Structure-based virtual screening; molecular docking; absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis; and molecular dynamics simulation were the methods applied for TMPRSS2 and spike protein inhibitors. Bioactive marine invertebrates from Indonesia were employed as test ligands. Camostat and nafamostat (co-crystal) were utilized as reference ligands against TMPRSS2, whereas mefloquine was used as a reference ligand against spike protein. Following a molecular docking and dynamics simulation, we found that acanthomanzamine C has remarkable effectiveness against TMPRSS2 and spike protein. Compared to camostat (-8.25 kcal/mol), nafamostat (-6.52 kcal/mol), and mefloquine (-6.34 kcal/mol), acanthomanzamine C binds to TMPRSS2 and spike protein with binding energies of -9.75 kcal/mol and -9.19 kcal/mol, respectively. Furthermore, slight variances in the MD simulation demonstrated consistent binding to TMPRSS2 and spike protein after the initial 50 ns. These results are highly valuable in the search for a treatment for SARS-CoV-2 infection.
Collapse
Affiliation(s)
| | - Alfrina Irene
- Faculty of Pharmacy Universitas Indonesia, Depok 16424, West Java, Indonesia
| | - Joko Tri Wibowo
- Research Center for Vaccine and Drug, National Research and Innovation Agency of Indonesia (BRIN), Cibinong, Indonesia
| | - Masteria Yunovilsa Putra
- Research Center for Vaccine and Drug, National Research and Innovation Agency of Indonesia (BRIN), Cibinong, Indonesia
- National Metabolomics Collaborative Research Center, Faculty of Pharmacy, Universitas Indonesia, Depok, 16424, West Java, Indonesia
| | - Arry Yanuar
- Faculty of Pharmacy Universitas Indonesia, Depok 16424, West Java, Indonesia
- National Metabolomics Collaborative Research Center, Faculty of Pharmacy, Universitas Indonesia, Depok, 16424, West Java, Indonesia
| |
Collapse
|
12
|
Chang YJ, Le UNP, Liu JJ, Li SR, Chao ST, Lai HC, Lin YF, Hsu KC, Lu CH, Lin CW. Combining virtual screening with cis-/trans-cleavage enzymatic assays effectively reveals broad-spectrum inhibitors that target the main proteases of SARS-CoV-2 and MERS-CoV. Antiviral Res 2023; 216:105653. [PMID: 37321487 PMCID: PMC10264167 DOI: 10.1016/j.antiviral.2023.105653] [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: 02/21/2023] [Revised: 05/23/2023] [Accepted: 06/04/2023] [Indexed: 06/17/2023]
Abstract
The main protease (Mpro) of SARS-CoV-2 is essential for viral replication, which suggests that the Mpro is a critical target in the development of small molecules to treat COVID-19. This study used an in-silico prediction approach to investigate the complex structure of SARS-CoV-2 Mpro in compounds from the United States National Cancer Institute (NCI) database, then validate potential inhibitory compounds against the SARS-CoV-2 Mpro in cis- and trans-cleavage proteolytic assays. Virtual screening of ∼280,000 compounds from the NCI database identified 10 compounds with highest site-moiety map scores. Compound NSC89640 (coded C1) showed marked inhibitory activity against the SARS-CoV-2 Mpro in cis-/trans-cleavage assays. C1 strongly inhibited SARS-CoV-2 Mpro enzymatic activity, with a half maximal inhibitory concentration (IC50) of 2.69 μM and a selectivity index (SI) of >74.35. The C1 structure served as a template to identify structural analogs based on AtomPair fingerprints to refine and verify structure-function associations. Mpro-mediated cis-/trans-cleavage assays conducted with the structural analogs revealed that compound NSC89641 (coded D2) exhibited the highest inhibitory potency against SARS-CoV-2 Mpro enzymatic activity, with an IC50 of 3.05 μM and a SI of >65.57. Compounds C1 and D2 also displayed inhibitory activity against MERS-CoV-2 with an IC50 of <3.5 μM. Thus, C1 shows potential as an effective Mpro inhibitor of SARS-CoV-2 and MERS-CoV. Our rigorous study framework efficiently identified lead compounds targeting the SARS-CoV-2 Mpro and MERS-CoV Mpro.
Collapse
Affiliation(s)
- Yu-Jen Chang
- The Ph.D. Program of Biotechnology and Biomedical Industry, China Medical University, Taichung, Taiwan
| | - Uyen Nguyen Phuong Le
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan; Graduate Institute of Biological Sciences and Technology, China Medical University, Taichung, Taiwan
| | - Jia-Jun Liu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Sin-Rong Li
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan; Department of Laboratory Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Shao-Ting Chao
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan
| | - Hsueh-Chou Lai
- Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Yu-Feng Lin
- Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan
| | - Kai-Cheng Hsu
- Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan
| | - Chih-Hao Lu
- The Ph.D. Program of Biotechnology and Biomedical Industry, China Medical University, Taichung, Taiwan; Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan; Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
| | - Cheng-Wen Lin
- The Ph.D. Program of Biotechnology and Biomedical Industry, China Medical University, Taichung, Taiwan; Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan; Graduate Institute of Biological Sciences and Technology, China Medical University, Taichung, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan.
| |
Collapse
|
13
|
Farkaš B, Minneci M, Misevicius M, Rozas I. A Tale of Two Proteases: M Pro and TMPRSS2 as Targets for COVID-19 Therapies. Pharmaceuticals (Basel) 2023; 16:834. [PMID: 37375781 PMCID: PMC10301481 DOI: 10.3390/ph16060834] [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: 04/27/2023] [Revised: 05/29/2023] [Accepted: 05/31/2023] [Indexed: 06/29/2023] Open
Abstract
Considering the importance of the 2019 outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulting in the coronavirus disease 2019 (COVID-19) pandemic, an overview of two proteases that play an important role in the infection by SARS-CoV-2, the main protease of SARS-CoV-2 (MPro) and the host transmembrane protease serine 2 (TMPRSS2), is presented in this review. After summarising the viral replication cycle to identify the relevance of these proteases, the therapeutic agents already approved are presented. Then, this review discusses some of the most recently reported inhibitors first for the viral MPro and next for the host TMPRSS2 explaining the mechanism of action of each protease. Afterward, some computational approaches to design novel MPro and TMPRSS2 inhibitors are presented, also describing the corresponding crystallographic structures reported so far. Finally, a brief discussion on a few reports found some dual-action inhibitors for both proteases is given. This review provides an overview of two proteases of different origins (viral and human host) that have become important targets for the development of antiviral agents to treat COVID-19.
Collapse
Affiliation(s)
| | | | | | - Isabel Rozas
- School of Chemistry, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, D02 R590 Dublin, Ireland; (B.F.); (M.M.); (M.M.)
| |
Collapse
|
14
|
Schlegel J, Porebski B, Andronico L, Hanke L, Edwards S, Brismar H, Murrell B, McInerney GM, Fernandez-Capetillo O, Sezgin E. A Multiparametric and High-Throughput Platform for Host-Virus Binding Screens. NANO LETTERS 2023; 23:3701-3707. [PMID: 36892970 PMCID: PMC10176574 DOI: 10.1021/acs.nanolett.2c04884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 05/11/2023]
Abstract
Speed is key during infectious disease outbreaks. It is essential, for example, to identify critical host binding factors to pathogens as fast as possible. The complexity of host plasma membrane is often a limiting factor hindering fast and accurate determination of host binding factors as well as high-throughput screening for neutralizing antimicrobial drug targets. Here, we describe a multiparametric and high-throughput platform tackling this bottleneck and enabling fast screens for host binding factors as well as new antiviral drug targets. The sensitivity and robustness of our platform were validated by blocking SARS-CoV-2 particles with nanobodies and IgGs from human serum samples.
Collapse
Affiliation(s)
- Jan Schlegel
- Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, 17165 Solna, Sweden
| | - Bartlomiej Porebski
- Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17165 Stockholm, Sweden
| | - Luca Andronico
- Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, 17165 Solna, Sweden
| | - Leo Hanke
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17165 Stockholm, Sweden
| | - Steven Edwards
- Science for Life Laboratory, Department of Applied Physics, Royal Institute of Technology, 17165 Solna, Sweden
| | - Hjalmar Brismar
- Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, 17165 Solna, Sweden
- Science for Life Laboratory, Department of Applied Physics, Royal Institute of Technology, 17165 Solna, Sweden
| | - Ben Murrell
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17165 Stockholm, Sweden
| | - Gerald M McInerney
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17165 Stockholm, Sweden
| | - Oscar Fernandez-Capetillo
- Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17165 Stockholm, Sweden
- Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain
| | - Erdinc Sezgin
- Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, 17165 Solna, Sweden
| |
Collapse
|
15
|
Cheng Y, Zheng D, Zhang D, Guo D, Wang Y, Liu W, Liang L, Hu J, Luo T. Molecular recognition of SARS-CoV-2 spike protein with three essential partners: exploring possible immune escape mechanisms of viral mutants. J Mol Model 2023; 29:109. [PMID: 36964244 PMCID: PMC10038388 DOI: 10.1007/s00894-023-05509-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/10/2022] [Accepted: 03/10/2023] [Indexed: 03/26/2023]
Abstract
OBJECTIVE The COVID-19 epidemic is raging around the world, with the emergence of viral mutant strains such as Delta and Omicron, posing severe challenges to people's health and quality of life. A full understanding life cycle of the virus in host cells helps to reveal inactivation mechanism of antibody and provide inspiration for the development of a new-generation vaccines. METHODS In this work, molecular recognitions and conformational changes of SARS-CoV-2 spike protein mutants (i.e., Delta, Mu, and Omicron) and three essential partners (i.e., membrane receptor hACE2, protease TMPRSS2, and antibody C121) both were compared and analyzed using molecular simulations. RESULTS Water basin and binding free energy calculations both show that the three mutants possess higher affinity for hACE2 than WT, exhibiting stronger virus transmission. The descending order of cleavage ability by TMPRSS2 is Mu, Delta, Omicron, and WT, which is related to the new S1/S2 cutting site induced by transposition effect. The inefficient utilization of TMPRSS2 by Omicron is consistent with its primary entry into cells via the endosomal pathway. In addition, RBD-directed antibody C121 showed obvious resistance to Omicron, which may have originated from high fluctuation of approaching angles, high flexibility of I472-F490 loop, and reduced binding ability. CONCLUSIONS According to the overall characteristics of the three mutants, high infectivity, high immune escape, and low virulence may be the future evolutionary selection of SARS-CoV-2. In a word, this work not only proposes the possible resistance mechanism of SARS-CoV-2 mutants, but also provides theoretical guidance for the subsequent drug design against COVID-19 based on S protein structure.
Collapse
Affiliation(s)
- Yan Cheng
- Breast Disease Center, West China Hospital, Sichuan University, Cancer CenterChengdu, 610000, China
| | - Dan Zheng
- Breast Disease Center, West China Hospital, Sichuan University, Cancer CenterChengdu, 610000, China
| | - Derong Zhang
- School of Marxism, Chengdu Vocational & Technical College of Industry, Chengdu, China
| | - Du Guo
- Breast Disease Center, West China Hospital, Sichuan University, Cancer CenterChengdu, 610000, China
| | - Yueteng Wang
- Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu, China
| | - Wei Liu
- Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu, China
| | - Li Liang
- Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu, China
| | - Jianping Hu
- Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu, China
| | - Ting Luo
- Breast Disease Center, West China Hospital, Sichuan University, Cancer CenterChengdu, 610000, China.
| |
Collapse
|
16
|
Vazquez-Rodriguez S, Ramírez-Contreras D, Noriega L, García-García A, Sánchez-Gaytán BL, Melendez FJ, Castro ME, de Azevedo WF, González-Vergara E. Interaction of copper potential metallodrugs with TMPRSS2: A comparative study of docking tools and its implications on COVID-19. Front Chem 2023; 11:1128859. [PMID: 36778030 PMCID: PMC9909424 DOI: 10.3389/fchem.2023.1128859] [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: 12/21/2022] [Accepted: 01/17/2023] [Indexed: 01/28/2023] Open
Abstract
SARS-CoV-2 is the virus responsible for the COVID-19 pandemic. For the virus to enter the host cell, its spike (S) protein binds to the ACE2 receptor, and the transmembrane protease serine 2 (TMPRSS2) cleaves the binding for the fusion. As part of the research on COVID-19 treatments, several Casiopeina-analogs presented here were looked at as TMPRSS2 inhibitors. Using the DFT and conceptual-DFT methods, it was found that the global reactivity indices of the optimized molecular structures of the inhibitors could be used to predict their pharmacological activity. In addition, molecular docking programs (AutoDock4, Molegro Virtual Docker, and GOLD) were used to find the best potential inhibitors by looking at how they interact with key amino acid residues (His296, Asp 345, and Ser441) in the catalytic triad. The results show that in many cases, at least one of the amino acids in the triad is involved in the interaction. In the best cases, Asp435 interacts with the terminal nitrogen atoms of the side chains in a similar way to inhibitors such as nafamostat, camostat, and gabexate. Since the copper compounds localize just above the catalytic triad, they could stop substrates from getting into it. The binding energies are in the range of other synthetic drugs already on the market. Because serine protease could be an excellent target to stop the virus from getting inside the cell, the analyzed complexes are an excellent place to start looking for new drugs to treat COVID-19.
Collapse
Affiliation(s)
- Sergio Vazquez-Rodriguez
- Centro de Química del Instituto de Ciencias, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico
| | - Diego Ramírez-Contreras
- Centro de Química del Instituto de Ciencias, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico
| | - Lisset Noriega
- Laboratorio de Química Teórica, Depto. de Fisicoquímica, Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico,Departamento de Física Aplicada, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mérida, Mexico
| | - Amalia García-García
- Centro de Química del Instituto de Ciencias, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico,Departamento de Química Inorgánica, Facultad de Ciencias, Universidad de Granada, Granada, Spain
| | - Brenda L. Sánchez-Gaytán
- Centro de Química del Instituto de Ciencias, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico
| | - Francisco J. Melendez
- Laboratorio de Química Teórica, Depto. de Fisicoquímica, Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico
| | - María Eugenia Castro
- Centro de Química del Instituto de Ciencias, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico,*Correspondence: María Eugenia Castro, ; Enrique González-Vergara,
| | - Walter Filgueira de Azevedo
- Escola de Ciências da Saúde, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Enrique González-Vergara
- Centro de Química del Instituto de Ciencias, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico,*Correspondence: María Eugenia Castro, ; Enrique González-Vergara,
| |
Collapse
|
17
|
Nejat R, Torshizi MF, Najafi DJ. S Protein, ACE2 and Host Cell Proteases in SARS-CoV-2 Cell Entry and Infectivity; Is Soluble ACE2 a Two Blade Sword? A Narrative Review. Vaccines (Basel) 2023; 11:204. [PMID: 36851081 PMCID: PMC9968219 DOI: 10.3390/vaccines11020204] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/01/2022] [Revised: 01/07/2023] [Accepted: 01/12/2023] [Indexed: 01/19/2023] Open
Abstract
Since the spread of the deadly virus SARS-CoV-2 in late 2019, researchers have restlessly sought to unravel how the virus enters the host cells. Some proteins on each side of the interaction between the virus and the host cells are involved as the major contributors to this process: (1) the nano-machine spike protein on behalf of the virus, (2) angiotensin converting enzyme II, the mono-carboxypeptidase and the key component of renin angiotensin system on behalf of the host cell, (3) some host proteases and proteins exploited by SARS-CoV-2. In this review, the complex process of SARS-CoV-2 entrance into the host cells with the contribution of the involved host proteins as well as the sequential conformational changes in the spike protein tending to increase the probability of complexification of the latter with angiotensin converting enzyme II, the receptor of the virus on the host cells, are discussed. Moreover, the release of the catalytic ectodomain of angiotensin converting enzyme II as its soluble form in the extracellular space and its positive or negative impact on the infectivity of the virus are considered.
Collapse
Affiliation(s)
- Reza Nejat
- Department of Anesthesiology and Critical Care Medicine, Laleh Hospital, Tehran 1467684595, Iran
| | | | | |
Collapse
|
18
|
Juthi RT, Sazed SA, Sarmin M, Haque R, Alam MS. COVID-19 and diarrhea: putative mechanisms and management. Int J Infect Dis 2023; 126:125-131. [PMID: 36403817 PMCID: PMC9672967 DOI: 10.1016/j.ijid.2022.11.018] [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: 09/16/2022] [Revised: 11/08/2022] [Accepted: 11/13/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19), has recently posed a threat to global health by spreading at a high rate and taking millions of lives worldwide. Along with the respiratory symptoms, there are gastrointestinal manifestations and one of the most common gastrointestinal symptoms is diarrhea which is seen in a significant percentage of COVID-19 patients. LITERATURE REVIEW Several studies have shown the plausible correlation between overexpressed angiotensin converting enzyme 2 (ACE2) in enterocytes and SARS-CoV-2, as ACE2 is the only known receptor for the virus entry. Along with the dysregulated ACE2, there are other contributing factors such as gut microbiome dysbiosis, adverse effects of antiviral and antibiotics for treating infections and inflammatory response to SARS-CoV-2 which bring about increased permeability of gut cells and subsequent occurrence of diarrhea. Few studies found that the SARS-CoV-2 is capable of damaging liver cells too. No single effective treatment option is available. LIMITATIONS Confirmed pathophysiology is still unavailable. Studies regarding global population are also insufficient. CONCLUSION In this review, based on the previous works and literature, we summarized the putative molecular pathophysiology of COVID-19 associated diarrhea, concomitant complications and the standard practices of management of diarrhea and hepatic manifestations in international setups.
Collapse
Affiliation(s)
- Rifat Tasnim Juthi
- Infectious Diseases Division, International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh
| | - Saiful Arefeen Sazed
- Infectious Diseases Division, International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh
| | - Monira Sarmin
- Nutrition and Clinical Services Division, International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh
| | - Rashidul Haque
- Infectious Diseases Division, International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh
| | - Mohammad Shafiul Alam
- Infectious Diseases Division, International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh,Corresponding author. Mohammad Shafiul Alam, Scientist, Infectious Diseases Division, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), 68 Shaheed Tajuddin Ahmed Sarani, Mohakhali, Dhaka-1212, Bangladesh. Tel: +8801711-469232
| |
Collapse
|
19
|
Kashyap D, Jakhmola S, Tiwari D, Kumar R, Moorthy NSHN, Elangovan M, Brás NF, Jha HC. Plant derived active compounds as potential anti SARS-CoV-2 agents: an in-silico study. J Biomol Struct Dyn 2022; 40:10629-10650. [PMID: 34225565 DOI: 10.1080/07391102.2021.1947384] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/18/2022]
Abstract
Plants are a valued potential source of drugs for a variety of diseases and are often considered less toxic to humans. We investigated antiviral compounds that may potentially target SARS-CoV-2 antigenic spike (S) and host proteins; angiotensin-converting enzyme2 (ACE2), and transmembrane serine protease2 (TMPRSS2). We scrutinized 36 phytochemicals from 15 Indian medicinal plants known to be effective against RNA viruses via molecular docking. Besides, the TMPRSS2 structure was modeled and validated using the SWISS-MODEL. Docking was performed using Autodock Vina and 4.2 followed by visualization of the docking poses on Pymol version 2.4.0 and Discovery Studio Visualizer. Molecular docking showed that 12 out of 36 active compounds interacted efficiently with S, ACE2, and TMPRSS2 proteins. The ADMET profile generated using the swissADME and pkCSM server revealed that these compounds were possessed druggable properties. The Amber 12 simulation package was used to carry out energy minimizations and molecular dynamics (MD) simulations. The total simulation time for both S protein: WFA and S protein: WND complexes was 300 ns (100 ns per replica). A total of 120 structures were extracted from the last 60 ns of each MD simulation for further analysis. MM-PBSA and MM-GBSA were employed to assess the binding energy of each ligand and the receptor-binding domain of the viral S-protein. The methods suggested that WND and WFA showed thermodynamically favorable binding energies, and the S protein had a higher affinity with WND. Interestingly, Leu455 hotspot residue in the S protein, also predicted to participate in binding with ACE2, was engaged by WND and WFA. HighlightsPlants' natural active compounds may aid in the development of COVID-19 therapeutics.MD simulation study revealed stable binding of withanolide D and withaferin A with spike proteinWithanolide D and withaferin A could be effective against SARS-CoV-2 spike protein.Discovery of druggable agents that have less or lack of binding affinity with ACE2 to avoid the organs associated with comorbidities.According to ADMET selected phytochemicals may be used as druggable compounds.Communicated by Ramaswamy H. Sarma.
Collapse
Affiliation(s)
- Dharmendra Kashyap
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, India
| | - Shweta Jakhmola
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, India
| | - Deeksha Tiwari
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, India
| | - Rajesh Kumar
- Department of Physics, Indian Institute of Technology Indore, Indore, India
| | | | | | - Natércia F Brás
- LAQV, REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Porto, Portugal
| | - Hem Chandra Jha
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, India
| |
Collapse
|
20
|
Akbasheva OE, Spirina LV, Dyakov DA, Masunova NV. Proteolysis and Deficiency of α1-Proteinase Inhibitor in SARS-CoV-2 Infection. BIOCHEMISTRY (MOSCOW) SUPPLEMENT. SERIES B, BIOMEDICAL CHEMISTRY 2022; 16:271-291. [PMID: 36407837 PMCID: PMC9668222 DOI: 10.1134/s1990750822040035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Academic Contribution Register] [Received: 02/02/2022] [Revised: 03/30/2022] [Accepted: 04/11/2022] [Indexed: 11/17/2022]
Abstract
The SARS-CoV-2 pandemic had stimulated the emergence of numerous publications on the α1-proteinase inhibitor (α1-PI, α1-antitrypsin), especially when it was found that the regions of high mortality corresponded to the regions with deficient α1-PI alleles. By analogy with the data obtained in the last century, when the first cause of the genetic deficiency of α1-antitrypsin leading to elastase activation in pulmonary emphysema was proven, it can be supposed that proteolysis hyperactivation in COVID-19 may be associated with the impaired functions of α1-PI. The purpose of this review was to systematize the scientific data and critical directions for translational studies on the role of α1-PI in SARS-CoV-2-induced proteolysis hyperactivation as a diagnostic marker and a therapeutic target. This review describes the proteinase-dependent stages of viral infection: the reception and penetration of the virus into a cell and the imbalance of the plasma aldosterone-angiotensin-renin, kinin, and blood clotting systems. The role of ACE2, TMPRSS, ADAM17, furin, cathepsins, trypsin- and elastase-like serine proteinases in the virus tropism, the activation of proteolytic cascades in blood, and the COVID-19-dependent complications is considered. The scientific reports on α1-PI involvement in the SARS-CoV-2-induced inflammation, the relationship with the severity of infection and comorbidities were analyzed. Particular attention is paid to the acquired α1-PI deficiency in assessing the state of patients with proteolysis overactivation and chronic non-inflammatory diseases, which are accompanied by the risk factors for comorbidity progression and the long-term consequences of COVID-19. Essential data on the search and application of protease inhibitor drugs in the therapy for bronchopulmonary and cardiovascular pathologies were analyzed. The evidence of antiviral, anti-inflammatory, anticoagulant, and anti-apoptotic effects of α1-PI, as well as the prominent data and prospects for its application as a targeted drug in the SARS-CoV-2 acquired pneumonia and related disorders, are presented.
Collapse
Affiliation(s)
| | - L. V. Spirina
- Siberian State Medical University, 634050 Tomsk, Russia
- Cancer Research Institute, Tomsk National Research Medical Center, 634009 Tomsk, Russia
| | - D. A. Dyakov
- Siberian State Medical University, 634050 Tomsk, Russia
| | | |
Collapse
|
21
|
Yan ZS, Li XL, Ma YQ, Ding HM. Effect of the Graphene Nanosheet on Functions of the Spike Protein in Open and Closed States: Comparison between SARS-CoV-2 Wild Type and the Omicron Variant. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2022; 38:13972-13982. [PMID: 36318181 PMCID: PMC9662070 DOI: 10.1021/acs.langmuir.2c02316] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 08/26/2022] [Revised: 10/05/2022] [Indexed: 05/24/2023]
Abstract
The spread of coronavirus disease 2019 caused by SARS-CoV-2 and its variants has become a global health crisis. Although there were many attempts to use nanomaterials-based devices to fight against SARS-CoV-2, it still remains elusive as to how the nanomaterials interact with SARS-CoV-2 and affect its biofunctions. Here, taking the graphene nanosheet (GN) as the model nanomaterial, we investigate its interaction with the spike protein in both WT and Omicron by molecular simulations. In the closed state, the GN can insert into the region between the receptor binding domain (RBD) and the N-terminal domain (NTD) in both wild type (WT) and Omicron, which keeps the RBD in the down conformation. In the open state, the GN can hamper the binding of up RBD to ACE2 in WT, but it has little impact on up RBD and, even worse, stimulates the down-to-up transition of down RBDs in Omicron. Moreover, the GN can insert in the vicinity of the fusion peptide in both WT and Omicron and prevents the detachment of S1 from the whole spike protein. The present study reveals the effect of the SARS-CoV-2 variant on the nanomaterial-spike protein interaction, which informs prospective efforts to design functional nanomaterials against SARS-CoV-2.
Collapse
Affiliation(s)
- Zeng-Shuai Yan
- National
Laboratory of Solid State Microstructures and Department of Physics,
Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing 210093, China
| | - Xiao-Lei Li
- National
Laboratory of Solid State Microstructures and Department of Physics,
Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing 210093, China
| | - Yu-Qiang Ma
- National
Laboratory of Solid State Microstructures and Department of Physics,
Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing 210093, China
| | - Hong-Ming Ding
- Center
for Soft Condensed Matter Physics and Interdisciplinary Research,
School of Physical Science and Technology, Soochow University, Suzhou 215006, China
| |
Collapse
|
22
|
Mahgoub MA, Alnaem A, Fadlelmola M, Abo-Idris M, Makki AA, Abdelgadir AA, Alzain AA. Discovery of novel potential inhibitors of TMPRSS2 and Mpro of SARS-CoV-2 using E-pharmacophore and docking-based virtual screening combined with molecular dynamic and quantum mechanics. J Biomol Struct Dyn 2022:1-14. [PMID: 35997154 DOI: 10.1080/07391102.2022.2112080] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/18/2023]
Abstract
The pandemic of coronavirus disease is caused by the SARS-CoV-2 which is considered a global health issue. The main protease of COVID 19 (Mpro) has an important role in viral multiplication in the host cell. Inhibiting Mpro is a novel approach to drug discovery and development. Also, transmembrane serine proteases (TMPSS2) facilitate viral activation by cleavage S glycoproteins, thus considered one of the essential host factors for COVID-19 pathogenicity. Computational tools were widely used to reduce time and costs in search of effective inhibitors. A chemical library that contains over two million molecules was virtually screened against TMPRSS2. Also, XP docking for the top hits was screened against (Mpro) to identify dual-target inhibitors. Furthermore, MM-GBSA and predictive ADMET were performed. The top hits were further studied through density functional theory (DFT) calculation and showed good binding to the active sites. Moreover, molecular dynamics (MD) for the top hits were performed which gave information about the stability of the protein-ligand complex during the simulation period. This study has led to the discovery of potential dual-target inhibitors Z751959696, Z751954014, and Z56784282 for COVID-19 with acceptable pharmacokinetic properties. The outcome of this study can participate in the development of novel inhibitors to defeat SARS-CoV-2.Communicated by Ramaswamy H. Sarma.
Collapse
Affiliation(s)
- Mohanad A Mahgoub
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Gezira, Sudan
| | - Ahmed Alnaem
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Gezira, Sudan
| | - Mohammed Fadlelmola
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Gezira, Sudan
| | - Mazin Abo-Idris
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Gezira, Sudan
| | - Alaa A Makki
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Gezira, Sudan
| | | | - Abdulrahim A Alzain
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Gezira, Sudan
| |
Collapse
|
23
|
Jain M, Anand A, Shah A. Exploring the Potential Role of Theaflavin-3,3′-Digallate in Inhibiting Various Stages of SARS-CoV-2 Life Cycle: An In-Silico Approach. CHEMISTRY AFRICA 2022. [PMCID: PMC9219385 DOI: 10.1007/s42250-022-00376-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Indexed: 12/13/2022]
Abstract
Introduction Theaflavins belong to the class of polyphenols that are predominantly found in black tea. The major derivatives of theaflavins found in black tea are theaflavin (TF1), theaflavin-3-gallate (TF2A), theaflavin-3′-gallate (TF2B), and theaflavin-3,3′-digallate (TF3). Theaflavin-3,3′-digallate (TF3) is a natural compound present in black tea and known to possess antiviral activity. This study had attempted to explore the potential role of TF3 in inhibiting various stages of the SARS-CoV-2 life cycle. Methods Molecular docking studies of TF3 along with positive controls was performed on eight different targets of SARS-CoV-2 followed by binding free energy (MM-GBSA) calculations. The docked complexes with favourable docking and binding free energy results were subjected to molecular dynamics (MD) simulation studies to assess the stability of the dock complex. Finally, TF3 and all the positive controls were taken for ADMET analysis. Results The docking and binding free energy results of TF3 was compared against the positive controls. TF3 showed the highest binding energy against all the targets and formed more stable interactions for a longer duration on MD simulations with CLpro, RdRp, helicase and spike protein. Also, the promising in-silico ADMET profile further warrants the exploration of this compound through in-vitro and in-vivo methods. Conclusion Through this study, we tried to evaluate the role of theaflavin-3,3’-digallate on multiple targets of SARS-CoV-2, and the positive in-silico results which were obtained on various pharmacodynamic and pharmacokinetic parameters, give a ray of hope as a potential therapeutic drug to this rapidly spreading disease. The search for a curative therapy for SARS-CoV-2 is still ongoing. The favourable preliminary results of TF3 through in-silico analysis offers a ray of hope in ending this devasting pandemic. Supplementary Information The online version contains supplementary material available at 10.1007/s42250-022-00376-7.
Collapse
Affiliation(s)
- Manav Jain
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, Punjab India
| | - Aishwarya Anand
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, Punjab India
| | - Ashish Shah
- Department of Pharmacy, Sumandeep Vidyapeeth, Vadodara, Gujarat India
| |
Collapse
|
24
|
Konduru GV, Nagarajaram HA. Human TMPRSS2 non-catalytic ectodomain and SARS-CoV-2 S2' subunit interaction mediated SARS-CoV-2 endocytosis: a model proposal with virtual screening for potential drug molecules to inhibit this interaction. J Biomol Struct Dyn 2022:1-12. [PMID: 35912718 DOI: 10.1080/07391102.2022.2105956] [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] [Indexed: 10/16/2022]
Abstract
This study proposes a novel model for integration of SARS-CoV-2 into host cell via endocytosis as a possible alternative to the prevailing direct fusion model. It is known that the SARS-CoV-2 spike protein undergoes proteolytic cleavage at S1-S2 cleavage site and the cleaved S2 domain is primed by the activated serine protease domain (SPD) of humanTMPRSS2 to become S2'. The activated SPD of TMPRSS2 is formed after it is cleaved by autocatalysis from the membrane bound non-catalytic ectodomain (hNECD) comprising of LDLRA CLASS-I repeat and a SRCR domain. It is known that the SRCR domains as well as LDLRA repeat harboring proteins mediate endocytosis of viruses and certain ligands. Based on this, we put forward a hypothesis that the exposed hNECD binds to the S2' as both are at an interaction proximity soon after S2 is processed by the SPD and this interaction may lead to the endocytosis of virus. Based on this hypothesis we have modelled the hNECD structure, followed by docking studies with the known 3D structure of S2'. The interaction interface of hNECD with S2' was further used for virtual screening of FDA-approved drug molecules and Indian medicinal plant-based compounds. We also mapped the known mutations of concern and mutations of interest on interaction interface of S2' and found that none of the known mutations map onto the interaction interface. This indicates that targeting the interaction between the hNECD of TMPRSS2 and S2' may serve as an attractive therapeutic target.Communicated by Ramaswamy H. Sarma.
Collapse
Affiliation(s)
- Guruprasad Varma Konduru
- Laboratory of Computational Biology, Centre for DNA Fingerprinting and Diagnostics, Uppal, Hyderabad, India.,Graduate Studies, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | | |
Collapse
|
25
|
(+)-Usnic acid and its salts, inhibitors of SARS-CoV-2, identified by using in silico methods and in vitro assay. Sci Rep 2022; 12:13118. [PMID: 35908082 PMCID: PMC9338942 DOI: 10.1038/s41598-022-17506-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/15/2022] [Accepted: 07/26/2022] [Indexed: 01/18/2023] Open
Abstract
The pandemic caused by severe acute respiratory Coronavirus-2 (SARS-CoV-2) has been ongoing for over two years, and treatment for COVID-19, other than monoclonal antibodies, is urgently required. Accordingly, we have investigated the inhibitors of SARS-CoV-2 protein targets by high-throughput virtual screening using a marine natural products database. Considering the calculated molecular properties and availability of the compounds, (+)-usnic acid was selected as a suitable hit. In the in vitro antiviral assay of (+)-usnic acid by the immunofluorescence method, IC50 was 7.99 μM, which is similar to that of remdesivir used as a positive control. The generalized Born and surface area continuum solvation (MM/GBSA) method was performed to find the potent target of (+)-usnic acid, and the Mpro protein showed the most prominent value, -52.05 kcal/mol, among other SARS-CoV-2 protein targets. Thereafter, RMSD and protein-ligand interactions were profiled using molecular dynamics (MD) simulations. Sodium usnate (NaU) improved in vitro assay results with an IC50 of 5.33 μM and a selectivity index (SI) of 9.38. Additionally, when (+)-usnic acid was assayed against SARS-CoV-2 variants, it showed enhanced efficacy toward beta variants with an IC50 of 2.92 μM and SI of 11.1. We report the in vitro anti-SARS-CoV-2 efficacy of (+)-usnic acid in this study and propose that it has the potential to be developed as a COVID-19 treatment if its in vivo efficacy has been confirmed.
Collapse
|
26
|
Study of protease-mediated processes initiating viral infection and cell-cell viral spreading of SARS-CoV-2. J Mol Model 2022; 28:224. [PMID: 35854129 PMCID: PMC9296015 DOI: 10.1007/s00894-022-05206-8] [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: 05/19/2022] [Accepted: 06/27/2022] [Indexed: 11/01/2022]
Abstract
Viral-cell entry and cell-cell viral spreading processes of SARS-CoV-2 are subjected to fast evolutionary optimization because of its worldwide spreading, requiring the need for new drug developments. However, this task is still challenging, because a detailed understanding of the underlying molecular processes, mediated by the key cellular proteases TMPRSS2 and furin, is still lacking. Here, we show by large-scale atomistic calculations that binding of the ACE2 cell receptor at one of the heteromers of the SARS-CoV-2 spike leads to a release of its furin cleavage site (S1/S2), enabling an enhanced furin binding, and that this latter process promotes the binding of TMPRSS2 through the release of the TMPRSS2 cleavage site (S2') out of the ACE2-binding heteromer. Moreover, we find that, after proteolytic cleavage, improved furin binding causes that parts of the S2 subunit dissociate from the complex, suggesting that furin promotes the fusion of the S2 subunit with the cell membrane before transfer of the viral RNA. Here we show by computational means that binding of the ACE2-cell receptor at one of the heteromers of the SARS-CoV-2 spike leads to an enhanced binding of the protease furin, promoting the binding of the protease TMPRSS2. Moreover, we show that, after proteolytic cleavage, improved furin binding causes that parts of the heteromer dissociate from the spike.
Collapse
|
27
|
Ahmed F, Lee JW, Samantasinghar A, Kim YS, Kim KH, Kang IS, Memon FH, Lim JH, Choi KH. SperoPredictor: An Integrated Machine Learning and Molecular Docking-Based Drug Repurposing Framework With Use Case of COVID-19. Front Public Health 2022; 10:902123. [PMID: 35784208 PMCID: PMC9244710 DOI: 10.3389/fpubh.2022.902123] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/22/2022] [Accepted: 05/02/2022] [Indexed: 12/13/2022] Open
Abstract
The global spread of the SARS coronavirus 2 (SARS-CoV-2), its manifestation in human hosts as a contagious disease, and its variants have induced a pandemic resulting in the deaths of over 6,000,000 people. Extensive efforts have been devoted to drug research to cure and refrain the spread of COVID-19, but only one drug has received FDA approval yet. Traditional drug discovery is inefficient, costly, and unable to react to pandemic threats. Drug repurposing represents an effective strategy for drug discovery and reduces the time and cost compared to de novo drug discovery. In this study, a generic drug repurposing framework (SperoPredictor) has been developed which systematically integrates the various types of drugs and disease data and takes the advantage of machine learning (Random Forest, Tree Ensemble, and Gradient Boosted Trees) to repurpose potential drug candidates against any disease of interest. Drug and disease data for FDA-approved drugs (n = 2,865), containing four drug features and three disease features, were collected from chemical and biological databases and integrated with the form of drug-disease association tables. The resulting dataset was split into 70% for training, 15% for testing, and the remaining 15% for validation. The testing and validation accuracies of the models were 99.3% for Random Forest and 99.03% for Tree Ensemble. In practice, SperoPredictor identified 25 potential drug candidates against 6 human host-target proteomes identified from a systematic review of journals. Literature-based validation indicated 12 of 25 predicted drugs (48%) have been already used for COVID-19 followed by molecular docking and re-docking which indicated 4 of 13 drugs (30%) as potential candidates against COVID-19 to be pre-clinically and clinically validated. Finally, SperoPredictor results illustrated the ability of the platform to be rapidly deployed to repurpose the drugs as a rapid response to emergent situations (like COVID-19 and other pandemics).
Collapse
Affiliation(s)
- Faheem Ahmed
- Department of Mechatronics Engineering, Jeju National University, Jeju, South Korea
| | - Jae Wook Lee
- Department of Mechatronics Engineering, Jeju National University, Jeju, South Korea
- BioSpero, Inc., Jeju, South Korea
| | | | | | - Kyung Hwan Kim
- Department of Mechatronics Engineering, Jeju National University, Jeju, South Korea
| | - In Suk Kang
- Department of Mechatronics Engineering, Jeju National University, Jeju, South Korea
| | - Fida Hussain Memon
- Department of Mechatronics Engineering, Jeju National University, Jeju, South Korea
| | - Jong Hwan Lim
- Department of Mechatronics Engineering, Jeju National University, Jeju, South Korea
| | - Kyung Hyun Choi
- Department of Mechatronics Engineering, Jeju National University, Jeju, South Korea
- BioSpero, Inc., Jeju, South Korea
| |
Collapse
|
28
|
Akbasheva OE, Spirina LV, Dyakov DA, Masunova NV. [Proteolysis and deficiency of α1-proteinase inhibitor in SARS-CoV-2 infection]. BIOMEDITSINSKAIA KHIMIIA 2022; 68:157-176. [PMID: 35717581 DOI: 10.18097/pbmc20226803157] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 06/15/2023]
Abstract
The SARS-CoV-2 pandemia had stimulated the numerous publications emergence on the α1-proteinase inhibitor (α1-PI, α1-antitrypsin), primarily when it was found that high mortality in some regions corresponded to the regions with deficient α1-PI alleles. By analogy with the last century's data, when the root cause of the α1-antitrypsin, genetic deficiency leading to the elastase activation in pulmonary emphysema, was proven. It is evident that proteolysis hyperactivation in COVID-19 may be associated with α1-PI impaired functions. The purpose of this review is to systematize scientific data, critical directions for translational studies on the role of α1-PI in SARS-CoV-2-induced proteolysis hyperactivation as a diagnostic marker and a target in therapy. This review describes the proteinase-dependent stages of a viral infection: the reception and virus penetration into the cell, the plasma aldosterone-angiotensin-renin, kinins, blood clotting systems imbalance. The ACE2, TMPRSS, ADAM17, furin, cathepsins, trypsin- and elastase-like serine proteinases role in the virus tropism, proteolytic cascades activation in blood, and the COVID-19-dependent complications is presented. The analysis of scientific reports on the α1-PI implementation in the SARS-CoV-2-induced inflammation, the links with the infection severity, and comorbidities were carried out. Particular attention is paid to the acquired α1-PI deficiency in assessing the patients with the proteolysis overactivation and chronic non-inflammatory diseases that are accompanied by the risk factors for the comorbidities progression, and the long-term consequences of COVID-19 initiation. Analyzed data on the search and proteases inhibitory drugs usage in the bronchopulmonary cardiovascular pathologies therapy are essential. It becomes evident the antiviral, anti-inflammatory, anticoagulant, anti-apoptotic effect of α1-PI. The prominent data and prospects for its application as a targeted drug in the SARS-CoV-2 acquired pneumonia and related disorders are presented.
Collapse
Affiliation(s)
| | - L V Spirina
- Siberian State Medical University, Tomsk, Russia; Cancer Research Institute, Tomsk National Research Medical Center, Tomsk, Russia
| | - D A Dyakov
- Siberian State Medical University, Tomsk, Russia
| | - N V Masunova
- Siberian State Medical University, Tomsk, Russia
| |
Collapse
|
29
|
Manjunathan R, Periyaswami V, Mitra K, Rosita AS, Pandya M, Selvaraj J, Ravi L, Devarajan N, Doble M. Molecular docking analysis reveals the functional inhibitory effect of Genistein and Quercetin on TMPRSS2: SARS-COV-2 cell entry facilitator spike protein. BMC Bioinformatics 2022; 23:180. [PMID: 35578172 PMCID: PMC9108711 DOI: 10.1186/s12859-022-04724-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/15/2021] [Accepted: 05/05/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The Transmembrane Serine Protease 2 (TMPRSS2) of human cell plays a significant role in proteolytic cleavage of SARS-Cov-2 coronavirus spike protein and subsequent priming to the receptor ACE2. Approaching TMPRSS2 as a therapeutic target for the inhibition of SARS-Cov-2 infection is highly promising. Hence, in the present study, we docked the binding efficacy of ten naturally available phyto compounds with known anti-viral potential with TMPRSS2. The aim is to identify the best phyto compound with a high functional affinity towards the active site of the TMPRSS2 with the aid of two different docking software. Molecular Dynamic Simulations were performed to analyse the conformational space of the binding pocket of the target protein with selected molecules. RESULTS Docking analysis using PyRx version 0.8 along with AutoDockVina reveals that among the screened phyto compounds, Genistein shows the maximum binding affinity towards the hydrophobic substrate-binding site of TMPRSS2 with three hydrogen bonds interaction ( - 7.5 kcal/mol). On the other hand, molecular docking analysis using Schrodinger identified Quercetin as the most potent phyto compound with a maximum binding affinity towards the hydrophilic catalytic site of TMPRSS2 ( - 7.847 kcal/mol) with three hydrogen bonds interaction. The molecular dynamics simulation reveals that the Quercetin-TMPRSS complex is stable until 50 ns and forms stable interaction with the protein ( - 22.37 kcal/mol of MM-PBSA binding free energy). Genistein creates a weak interaction with the loop residues and hence has an unstable binding and exits from the binding pocket. CONCLUSION The compounds, Quercetin and Genistein, can inhibit the TMPRSS2 guided priming of the spike protein. The compounds could reduce the interaction of the host cell with the type I transmembrane glycoprotein to prevent the entry of the virus. The critical finding is that compared to Genistein, Quercetin exhibits higher binding affinity with the catalytic unit of TMPRSS2 and forms a stable complex with the target. Thus, enhancing our innate immunity by consuming foods rich in Quercetin and Genistein or developing a novel drug in the combination of Quercetin and Genistein could be the brilliant choices to prevent SARS-Cov-2 infection when we consider the present chaos associated with vaccines and anti-viral medicines.
Collapse
Affiliation(s)
- Reji Manjunathan
- Department of Genetics, Dr. ALM Post Graduate Institute of Basic Medical Sciences, Taramani Campus, University of Madras, Chennai, Tamil Nadu, India. .,Multi-Disciplinary Research Unit, Chengalpattu Government Medical College and Hospital, Chengalpattu, Tamil Nadu, 603001, India.
| | - Vijayalakshmi Periyaswami
- Department of Biotechnology and Bioinformatics, Holy Cross College, Bharathidasan University, Trichy, Tamil Nadu, India
| | - Kartik Mitra
- Bioengineering and Drug Design Lab, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India
| | - Arokiaraj Sherlin Rosita
- Department of Bioinformatics, Bishop Heber College (Autonomous, Bharathidasan University), Tiruchirapalli, Tamil Nadu, India
| | - Medha Pandya
- KPES Science College, Maharaja KrishnakumarSinhiji Bhavnagar University, Gujarat, India
| | - Jayaraman Selvaraj
- Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
| | - Lokesh Ravi
- Department of Botany, St. Josephs College, Bangalore, Karnataka, India
| | - Nalini Devarajan
- Central Research Laboratory, Meenakshi Ammal Dental College, Maduravoyal, Chennai, Tamil Nadu, India.
| | - Mukesh Doble
- Bioengineering and Drug Design Lab, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India. .,Department of Cariology, Saveetha Dental College and Hospital, Chennai, Tamil Nadu, 600077, India.
| |
Collapse
|
30
|
Abstract
The ongoing coronavirus disease 2019 (COVID-19) pandemic demonstrates the threat posed by novel coronaviruses to human health. Coronaviruses share a highly conserved cell entry mechanism mediated by the spike protein, the sole product of the S gene. The structural dynamics by which the spike protein orchestrates infection illuminate how antibodies neutralize virions and how S mutations contribute to viral fitness. Here, we review the process by which spike engages its proteinaceous receptor, angiotensin converting enzyme 2 (ACE2), and how host proteases prime and subsequently enable efficient membrane fusion between virions and target cells. We highlight mutations common among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern and discuss implications for cell entry. Ultimately, we provide a model by which sarbecoviruses are activated for fusion competency and offer a framework for understanding the interplay between humoral immunity and the molecular evolution of the SARS-CoV-2 Spike. In particular, we emphasize the relevance of the Canyon Hypothesis (M. G. Rossmann, J Biol Chem 264:14587-14590, 1989) for understanding evolutionary trajectories of viral entry proteins during sustained intraspecies transmission of a novel viral pathogen.
Collapse
Affiliation(s)
- Kyle A. Wolf
- Department of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA
- Interdiscipinary Ph.D. Program in Structural and Computational Biology and Quantitative Biosciences, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Jason C. Kwan
- Department of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Jeremy P. Kamil
- Department of Microbiology and Immunology, Louisiana State University Health Shreveport, Shreveport, Louisiana, USA
- Center for Excellence in Emerging Viral Threats, Louisiana State University Health Shreveport, Shreveport, Louisiana, USA
| |
Collapse
|
31
|
Guo D, Duan H, Cheng Y, Wang Y, Hu J, Shi H. Omicron-included mutation-induced changes in epitopes of SARS-CoV-2 spike protein and effectiveness assessments of current antibodies. MOLECULAR BIOMEDICINE 2022; 3:12. [PMID: 35461370 PMCID: PMC9034971 DOI: 10.1186/s43556-022-00074-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/02/2022] [Accepted: 03/25/2022] [Indexed: 02/08/2023] Open
Abstract
The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading globally and continues to rage, posing a serious threat to human health and life quality. Antibody therapy and vaccines both have shown great efficacy in the prevention and treatment of COVID-19, whose development progress and adaptation range have attracted wide attention. However, with the emergence of variant strains of SARS-CoV-2, the neutralization activity of therapeutic or vaccine-induced antibodies may be reduced, requiring long-term virus monitoring and drug upgrade in response to its evolution. In this paper, conformational changes including continuous epitopes (CPs), discontinuous epitopes (DPs) and recognition interfaces of the three representative SARS-CoV-2 spike protein (SP) mutants (i.e., the Delta (B.1.617.2), Mu (B.1.621) and Omicron (B.1.1.529) strains), were analyzed to evaluate the effectiveness of current mainstream antibodies. The results showed that the conformation of SP wild type (WT) and mutants both remained stable, while the local antigenic epitopes underwent significant changes. Sufficient flexibility of SP CPs is critical for effective antibody recognition. The DPs of Delta, Mu and Omicron variants have showed stronger binding to human angiotensin converting enzyme-2 (hACE2) than WT; the possible drug resistance mechanisms of antibodies against three different epitopes (i.e., NTD_DP, RBD1_DP and RBD2_DP) were also proposed, respectively; the RBD2 of Delta, NTD of Mu, NTD and RBD2 of Omicron are deserve more attention in the subsequent design of next-generation vaccines. The simulation results not only revealed structural characteristics of SP antigenic epitopes, but also provided guidance for antibody modification, vaccine design and effectiveness evaluation.
Collapse
Affiliation(s)
- Du Guo
- Laboratory of Tumor Targeted and Immune Therapy, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China
| | - Huaichuan Duan
- Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu, 610106, China
| | - Yan Cheng
- Laboratory of Tumor Targeted and Immune Therapy, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China
| | - Yueteng Wang
- Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu, 610106, China
| | - Jianping Hu
- Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu, 610106, China.
| | - Hubing Shi
- Laboratory of Tumor Targeted and Immune Therapy, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China.
| |
Collapse
|
32
|
Rhoades R, Solomon S, Johnson C, Teng S. Impact of SARS-CoV-2 on Host Factors Involved in Mental Disorders. Front Microbiol 2022; 13:845559. [PMID: 35444632 PMCID: PMC9014212 DOI: 10.3389/fmicb.2022.845559] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/29/2021] [Accepted: 02/14/2022] [Indexed: 11/23/2022] Open
Abstract
COVID-19, caused by SARS-CoV-2, is a systemic illness due to its multiorgan effects in patients. The disease has a detrimental impact on respiratory and cardiovascular systems. One early symptom of infection is anosmia or lack of smell; this implicates the involvement of the olfactory bulb in COVID-19 disease and provides a route into the central nervous system. However, little is known about how SARS-CoV-2 affects neurological or psychological symptoms. SARS-CoV-2 exploits host receptors that converge on pathways that impact psychological symptoms. This systemic review discusses the ways involved by coronavirus infection and their impact on mental health disorders. We begin by briefly introducing the history of coronaviruses, followed by an overview of the essential proteins to viral entry. Then, we discuss the downstream effects of viral entry on host proteins. Finally, we review the literature on host factors that are known to play critical roles in neuropsychiatric symptoms and mental diseases and discuss how COVID-19 could impact mental health globally. Our review details the host factors and pathways involved in the cellular mechanisms, such as systemic inflammation, that play a significant role in the development of neuropsychological symptoms stemming from COVID-19 infection.
Collapse
Affiliation(s)
- Raina Rhoades
- Department of Biology, Howard University, Washington, DC, United States
| | - Sarah Solomon
- Department of Biology, Howard University, Washington, DC, United States
| | - Christina Johnson
- Department of Biology, Howard University, Washington, DC, United States
| | | |
Collapse
|
33
|
Uma Reddy B, Routhu NK, Kumar A. Multifaceted role of plant derived small molecule inhibitors on replication cycle of sars-cov-2. Microb Pathog 2022; 168:105512. [PMID: 35381324 PMCID: PMC8976571 DOI: 10.1016/j.micpath.2022.105512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/18/2022] [Revised: 03/27/2022] [Accepted: 03/30/2022] [Indexed: 11/15/2022]
Abstract
Introduction Coronavirus disease 2019 (COVID-19) is an illness caused by the new coronavirus severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). It has affected public health and the economy globally. Currently approved vaccines and other drug candidates could be associated with several drawbacks which urges developing alternative therapeutic approaches. Aim To provide a comprehensive review of anti-SARS-CoV-2 activities of plants and their bioactive compounds. Methods Information was gathered from diverse bibliographic platforms such as PubMed, Google Scholar, and ClinicalTrials.gov registry. Results The present review highlights the potential roles of crude extracts of plants as well as plant-derived small molecules in inhibiting SARS-CoV-2 infection by targeting viral or host factors essential for viral entry, polyprotein processing, replication, assembly and release. Their anti-inflammatory and antioxidant properties as well as plant-based therapies that are under development in the clinical trial phases-1 to 3 are also covered. Conclusion This knowledge could further help understanding SARS-CoV-2 infection and anti-viral mechanisms of plant-based therapeutics.
Collapse
Affiliation(s)
- B Uma Reddy
- Department of Studies in Botany, Vijayanagara Sri Krishnadevaraya University, Ballari, 583105, India.
| | - Nanda Kishore Routhu
- Emory Vaccine Center, Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
| | - Anuj Kumar
- Cancer Research Center of Lyon (CRCL), INSERM 1052, CNRS UMR 5286, Lyon, 69008, France.
| |
Collapse
|
34
|
Bentum K, Shaddox S, Ware C, Reddy G, Abebe W, Folitse R, Martin P, Samuel T. Molecular phylogeny of coronaviruses and host receptors among domestic and close-contact animals reveals subgenome-level conservation, crossover, and divergence. BMC Vet Res 2022; 18:124. [PMID: 35365153 PMCID: PMC8972689 DOI: 10.1186/s12917-022-03217-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/08/2021] [Accepted: 03/14/2022] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Coronaviruses have the potential to cross species barriers. To learn the molecular intersections among the most common coronaviruses of domestic and close-contact animals, we analyzed representative coronavirus genera infecting mouse, rat, rabbit, dog, cat, cattle, white-tailed deer, swine, ferret, mink, alpaca, Rhinolophus bat, dolphin, whale, chicken, duck and turkey hosts; reference or complete genome sequences were available for most of these coronavirus genera. Protein sequence alignments and phylogenetic trees were built for the spike (S), envelope (E), membrane (M) and nucleocapsid (N) proteins. The host receptors and enzymes aminopeptidase N (APN), angiotensin converting enzyme 2 (ACE2), sialic acid synthase (SAS), transmembrane serine protease 2 (TMPRSS2), dipeptidyl peptidase 4 (DPP4), cathepsin L (and its analogs) and furin were also compared. RESULTS Overall, the S, E, M, and N proteins segregated according to their viral genera (α, β, or γ), but the S proteins of alphacoronaviruses lacked conservation of phylogeny. Interestingly, the unique polybasic furin cleavage motif found in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) but not in severe acute respiratory syndrome coronavirus (SARS-CoV) or Middle East respiratory syndrome coronavirus (MERS-CoV) exists in several β-coronaviruses and a few α- or γ-coronaviruses. Receptors and enzymes retained host species-dependent relationships with one another. Among the hosts, critical ACE2 residues essential for SARS-CoV-2 spike protein binding were most conserved in white-tailed deer and cattle. CONCLUSION The polybasic furin cleavage motif found in several β- and other coronaviruses of animals points to the existence of an intermediate host for SARS-CoV-2, and it also offers a counternarrative to the theory of a laboratory-engineered virus. Generally, the S proteins of coronaviruses show crossovers of phylogenies indicative of recombination events. Additionally, the consistency in the segregation of viral proteins of the MERS-like coronavirus (NC_034440.1) from pipistrelle bat supports its classification as a β-coronavirus. Finally, similarities in host enzymes and receptors did not always explain natural cross-infections. More studies are therefore needed to identify factors that determine the cross-species infectivity of coronaviruses.
Collapse
Affiliation(s)
- Kingsley Bentum
- Department of Pathobiology, College of Veterinary Medicine, Patterson Hall, Tuskegee University, Patterson Hall, 1200 W. Montgomery Road, Tuskegee, AL, 36088, USA
| | - Sage Shaddox
- Department of Pathobiology, College of Veterinary Medicine, Patterson Hall, Tuskegee University, Patterson Hall, 1200 W. Montgomery Road, Tuskegee, AL, 36088, USA
| | - Crystal Ware
- Department of Pathobiology, College of Veterinary Medicine, Patterson Hall, Tuskegee University, Patterson Hall, 1200 W. Montgomery Road, Tuskegee, AL, 36088, USA
| | - Gopal Reddy
- Department of Pathobiology, College of Veterinary Medicine, Patterson Hall, Tuskegee University, Patterson Hall, 1200 W. Montgomery Road, Tuskegee, AL, 36088, USA
| | - Woubit Abebe
- Department of Pathobiology, College of Veterinary Medicine, Patterson Hall, Tuskegee University, Patterson Hall, 1200 W. Montgomery Road, Tuskegee, AL, 36088, USA
| | - Raphael Folitse
- School of Veterinary Medicine, Kwame Nkrumah University of Science and Technology, University Post Office, Kumasi, Ghana
| | - Pamela Martin
- Department of Pathobiology, College of Veterinary Medicine, Patterson Hall, Tuskegee University, Patterson Hall, 1200 W. Montgomery Road, Tuskegee, AL, 36088, USA
| | - Temesgen Samuel
- Department of Pathobiology, College of Veterinary Medicine, Patterson Hall, Tuskegee University, Patterson Hall, 1200 W. Montgomery Road, Tuskegee, AL, 36088, USA.
| |
Collapse
|
35
|
Comparative study of SARS-CoV-2 infection in different cell types: Biophysical-computational approach to the role of potential receptors. Comput Biol Med 2022; 142:105245. [PMID: 35077937 PMCID: PMC8770263 DOI: 10.1016/j.compbiomed.2022.105245] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/14/2021] [Revised: 01/07/2022] [Accepted: 01/16/2022] [Indexed: 12/17/2022]
Abstract
Cellular susceptibility to SARS-CoV-2 infection in the respiratory tract has been associated with the ability of the virus to interact with potential receptors on the host membrane. We have modeled viral dynamics by simulating various cellular systems and artificial conditions, including macromolecular crowding, based on experimental and transcriptomic data to infer parameters associated with viral growth and predict cell susceptibility. We have accomplished this based on the type, number and level of expression of the angiotensin-converting enzyme 2 (ACE2), transmembrane serine 2 (TMPRSS2), basigin2 (CD147), FURIN protease, neuropilin 1 (NRP1) or other less studied candidate receptors such as heat shock protein A5 (HSPA5) and angiotensin II receptor type 2 (AGTR2). In parallel, we studied the effect of simulated artificial environments on the accessibility to said proposed receptors. In addition, viral kinetic behavior dependent on the degree of cellular susceptibility was predicted. The latter was observed to be more influenced by the type of proteins and expression level, than by the number of potential proteins associated with the SARS CoV-2 infection. We predict a greater theoretical propensity to susceptibility in cell lines such as NTERA-2, SCLC-21H, HepG2 and Vero6, and a lower theoretical propensity in lines such as CaLu3, RT4, HEK293, A549 and U-251MG. An important relationship was observed between expression levels, protein diffusivity, and thermodynamically favorable interactions between host proteins and the viral spike, suggesting potential sites of early infection other than the lungs. This research is expected to stimulate future quantitative experiments and promote systematic investigation of the effect of crowding presented here.
Collapse
|
36
|
In Silico Molecular Characterization of Human TMPRSS2 Protease Polymorphic Variants and Associated SARS-CoV-2 Susceptibility. Life (Basel) 2022; 12:life12020231. [PMID: 35207518 PMCID: PMC8876804 DOI: 10.3390/life12020231] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/05/2022] [Revised: 01/19/2022] [Accepted: 01/31/2022] [Indexed: 12/11/2022] Open
Abstract
The 2019 coronavirus disease (COVID-19) pandemic continues to challenge health care systems worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been responsible for the cause of global pandemic. Type 2 transmembrane serine protease (TMPRSS2) is important in the cell entry and spread of SARS-CoV-2 and plays a crucial role in the proteolytic cleavage of SARS-CoV-2 spike (S) glycoprotein. Here, using reported structural data, we analyzed the molecular complex of TMPRSS2 and the S glycoprotein and further examined intermolecular interactions of natural TMPRSS2 polymorphic variants. We identified several TMPRSS2 variants that could possibly alter host susceptibility to the SARS-CoV-2 infection. Molecular docking analysis revealed that G462D/G462S variants were predicted to be protective variants, whereas Q438E and S339F variants were predicted to increase susceptibility. In addition, we examined intermolecular interactions between TMPRSS2 and its two potential serine protease inhibitors, camostat mesylate and nafamostat. Further, we investigated the effect of TMPRSS2 variants on these interactions. Our structural analysis revealed that G462D, C297S and S460R variants had possibly altered the interactions with the protease inhibitors. Our results identified important TMPRSS2 variations that could be useful to develop high affinity and personalized drugs for treating COVID-19 patients.
Collapse
|
37
|
Alzain AA, Elbadwi FA, Alsamani FO. Discovery of novel TMPRSS2 inhibitors for COVID-19 using in silico fragment-based drug design, molecular docking, molecular dynamics, and quantum mechanics studies. INFORMATICS IN MEDICINE UNLOCKED 2022; 29:100870. [PMID: 35128036 PMCID: PMC8806845 DOI: 10.1016/j.imu.2022.100870] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/17/2021] [Revised: 01/29/2022] [Accepted: 01/29/2022] [Indexed: 01/18/2023] Open
Abstract
The global expansion of COVID-19 and the mutations of severe acute respiratory syndrome coronavirus necessitate quick development of treatment and vaccination. Because the androgen-responsive serine protease TMPRSS2 is involved in cleaving the SARS-CoV-2 spike protein allowing the virus to enter the cell, therefore, direct TMPRSS2 inhibition will inhibit virus activation and disease progression which make it an important target for drug discovery. In this study, a homology model of TMPRSS2 protein was initially developed. Then, we used the fragment-based drug design (FBDD) technique to develop effective TMPRSS2 inhibitors. Over a half-million fragments from the enamine database were screened for their binding ability to target protein, and then best-scoring fragments were linked to building new molecules with a good binding affinity. XP docking and MM-GBSA studies revealed 10 new formed molecules with docking score ≤ -14.982 kcal/mol compared to ambroxol (control) with a docking score of -6.464 kcal/mol. Finally, molecular dynamics (MD) and density functional theory (DFT) were calculated for the top 3 molecules.
Collapse
Affiliation(s)
- Abdulrahim A Alzain
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Gezira, Sudan
| | - Fatima A Elbadwi
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Gezira, Sudan
| | - Fatima O Alsamani
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Gezira, Sudan
| |
Collapse
|
38
|
Pizzato M, Baraldi C, Boscato Sopetto G, Finozzi D, Gentile C, Gentile MD, Marconi R, Paladino D, Raoss A, Riedmiller I, Ur Rehman H, Santini A, Succetti V, Volpini L. SARS-CoV-2 and the Host Cell: A Tale of Interactions. FRONTIERS IN VIROLOGY 2022. [DOI: 10.3389/fviro.2021.815388] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 12/18/2022]
Abstract
The ability of a virus to spread between individuals, its replication capacity and the clinical course of the infection are macroscopic consequences of a multifaceted molecular interaction of viral components with the host cell. The heavy impact of COVID-19 on the world population, economics and sanitary systems calls for therapeutic and prophylactic solutions that require a deep characterization of the interactions occurring between virus and host cells. Unveiling how SARS-CoV-2 engages with host factors throughout its life cycle is therefore fundamental to understand the pathogenic mechanisms underlying the viral infection and to design antiviral therapies and prophylactic strategies. Two years into the SARS-CoV-2 pandemic, this review provides an overview of the interplay between SARS-CoV-2 and the host cell, with focus on the machinery and compartments pivotal for virus replication and the antiviral cellular response. Starting with the interaction with the cell surface, following the virus replicative cycle through the characterization of the entry pathways, the survival and replication in the cytoplasm, to the mechanisms of egress from the infected cell, this review unravels the complex network of interactions between SARS-CoV-2 and the host cell, highlighting the knowledge that has the potential to set the basis for the development of innovative antiviral strategies.
Collapse
|
39
|
Emrani J, Ahmed M, Jeffers-Francis L, Teleha JC, Mowa N, Newman RH, Thomas MD. SARS-COV-2, infection, transmission, transcription, translation, proteins, and treatment: A review. Int J Biol Macromol 2021; 193:1249-1273. [PMID: 34756970 PMCID: PMC8552795 DOI: 10.1016/j.ijbiomac.2021.10.172] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/30/2021] [Accepted: 10/21/2021] [Indexed: 01/18/2023]
Abstract
In this review, we describe the key molecular entities involved in the process of infection by SARS-CoV-2, while also detailing how those key entities influence the spread of the disease. We further introduce the molecular mechanisms of preventive and treatment strategies including drugs, antibodies, and vaccines.
Collapse
Affiliation(s)
- Jahangir Emrani
- Department of Chemistry, North Carolina A&T State University, Greensboro, NC 27411, United States of America.
| | - Maryam Ahmed
- Department of Biology, Appalachian State University, Boone, NC 28608, United States of America
| | - Liesl Jeffers-Francis
- Department of Biology, North Carolina A&T State University, Greensboro, NC 27411, United States of America
| | - John C Teleha
- Department of Reference and Instruction, North Carolina A&T State University, Greensboro, NC 27411, United States of America
| | - Nathan Mowa
- Department of Biology, Appalachian State University, Boone, NC 28608, United States of America
| | - Robert H Newman
- Department of Biology, North Carolina A&T State University, Greensboro, NC 27411, United States of America
| | - Misty D Thomas
- Department of Biology, North Carolina A&T State University, Greensboro, NC 27411, United States of America
| |
Collapse
|
40
|
Alzain AA, Elbadwi FA. Identification of novel TMPRSS2 inhibitors for COVID-19 using e-pharmacophore modelling, molecular docking, molecular dynamics and quantum mechanics studies. INFORMATICS IN MEDICINE UNLOCKED 2021; 26:100758. [PMID: 34667827 PMCID: PMC8516157 DOI: 10.1016/j.imu.2021.100758] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/27/2021] [Revised: 09/22/2021] [Accepted: 10/11/2021] [Indexed: 12/23/2022] Open
Abstract
SARS coronavirus 2 (SARS-CoV-2) has spread rapidly around the world and continues to have a massive global health effect, contributing to an infectious respiratory illness called coronavirus infection-19 (COVID-19). TMPRSS2 is an emerging molecular target that plays a role in the early stages of SARS-CoV-2 infection; hence, inhibiting its activity might be a target for COVID-19. This study aims to use many computational approaches to provide compounds that could be optimized into clinical candidates. As there is no experimentally derived protein information, initially we develop the TMPRSS2 model. Then, we generate a pharmacophore model from TMPRSS2 active site consequently, and the developed models were employed for the screening of one million molecules from the Enamine database. The created model was then screened using e-pharmacophore-based screening, molecular docking, free energy estimation and molecular dynamic simulation. Also, ADMET prediction and density functional theory calculations were performed. Three potential molecules (Z126202570, Z46489368, and Z422255982) exhibited promising stable binding interactions with the target. In conclusion, these findings empower further in vitro and clinical assessment for these compounds as novel anti-COVID19 agents.
Collapse
Affiliation(s)
- Abdulrahim A Alzain
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Gezira, Sudan
| | - Fatima A Elbadwi
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Gezira, Sudan
| |
Collapse
|
41
|
Saih A, Bouqdayr M, Baba H, Hamdi S, Moussamih S, Bennani H, Saile R, Wakrim L, Kettani A. Computational Analysis of Missense Variants in the Human Transmembrane Protease Serine 2 ( TMPRSS2) and SARS-CoV-2. BIOMED RESEARCH INTERNATIONAL 2021; 2021:9982729. [PMID: 34692848 PMCID: PMC8531787 DOI: 10.1155/2021/9982729] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 03/29/2021] [Revised: 07/06/2021] [Accepted: 09/11/2021] [Indexed: 01/08/2023]
Abstract
The human transmembrane protease serine 2 (TMPRSS2) protein plays an important role in prostate cancer progression. It also facilitates viral entry into target cells by proteolytically cleaving and activating the S protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the current study, we used different available tools like SIFT, PolyPhen2.0, PROVEAN, SNAP2, PMut, MutPred2, I-Mutant Suite, MUpro, iStable, ConSurf, ModPred, SwissModel, PROCHECK, Verify3D, and TM-align to identify the most deleterious variants and to explore possible effects on the TMPRSS2 stability, structure, and function. The six missense variants tested were evaluated to have deleterious effects on the protein by SIFT, PolyPhen2.0, PROVEAN, SNAP2, and PMut. Additionally, V160M, G181R, R240C, P335L, G432A, and D435Y variants showed a decrease in stability by at least 2 servers; G181R, G432A, and D435Y are highly conserved and identified posttranslational modifications sites (PTMs) for proteolytic cleavage and ADP-ribosylation using ConSurf and ModPred servers. The 3D structure of TMPRSS2 native and mutants was generated using 7 meq as a template from the SwissModeller group, refined by ModRefiner, and validated using the Ramachandran plot. Hence, this paper can be advantageous to understand the association between these missense variants rs12329760, rs781089181, rs762108701, rs1185182900, rs570454392, and rs867186402 and susceptibility to SARS-CoV-2.
Collapse
Affiliation(s)
- Asmae Saih
- Virology Unit, Immunovirology Laboratory, Institut Pasteur du Maroc, 20360 Casablanca, Morocco
- Laboratory of Biology and Health, URAC 34, Faculty of Sciences Ben M'Sik Hassan II University of Casablanca, Morocco
| | - Meryem Bouqdayr
- Virology Unit, Immunovirology Laboratory, Institut Pasteur du Maroc, 20360 Casablanca, Morocco
- Laboratory of Biology and Health, URAC 34, Faculty of Sciences Ben M'Sik Hassan II University of Casablanca, Morocco
| | - Hanâ Baba
- Virology Unit, Immunovirology Laboratory, Institut Pasteur du Maroc, 20360 Casablanca, Morocco
- Laboratory of Biology and Health, URAC 34, Faculty of Sciences Ben M'Sik Hassan II University of Casablanca, Morocco
| | - Salsabil Hamdi
- Environmental Health Laboratory, Institut Pasteur du Maroc, 20360 Casablanca, Morocco
| | - Samya Moussamih
- Immunology and Biodiversity Laboratory, Faculty of Sciences Ain Chock, Hassan II University of Casablanca, Morocco
| | - Houda Bennani
- Laboratory of Biology and Health, URAC 34, Faculty of Sciences Ben M'Sik Hassan II University of Casablanca, Morocco
| | - Rachid Saile
- Laboratory of Biology and Health, URAC 34, Faculty of Sciences Ben M'Sik Hassan II University of Casablanca, Morocco
| | - Lahcen Wakrim
- Virology Unit, Immunovirology Laboratory, Institut Pasteur du Maroc, 20360 Casablanca, Morocco
| | - Anass Kettani
- Laboratory of Biology and Health, URAC 34, Faculty of Sciences Ben M'Sik Hassan II University of Casablanca, Morocco
| |
Collapse
|
42
|
Kumar S, Çalışkan DM, Janowski J, Faist A, Conrad BCG, Lange J, Ludwig S, Brunotte L. Beyond Vaccines: Clinical Status of Prospective COVID-19 Therapeutics. Front Immunol 2021; 12:752227. [PMID: 34659259 PMCID: PMC8519339 DOI: 10.3389/fimmu.2021.752227] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/02/2021] [Accepted: 09/14/2021] [Indexed: 12/15/2022] Open
Abstract
Since November 2019 the SARS-CoV-2 pandemic has caused nearly 200 million infection and more than 4 million deaths globally (Updated information from the World Health Organization, as on 2nd Aug 2021). Within only one year into the pandemic, several vaccines were designed and reached approval for the immunization of the world population. The remarkable protective effects of the manufactured vaccines are demonstrated in countries with high vaccination rates, such as Israel and UK. However, limited production capacities, poor distribution infrastructures and political hesitations still hamper the availability of vaccines in many countries. In addition, due to the emergency of SARS-CoV-2 variants with immune escape properties towards the vaccines the global numbers of new infections as well as patients developing severe COVID-19, remains high. New studies reported that about 8% of infected individuals develop long term symptoms with strong personal restrictions on private as well as professional level, which contributes to the long socioeconomic problems caused by this pandemic. Until today, emergency use-approved treatment options for COVID-19 are limited to the antiviral Remdesivir, a nucleoside analogue targeting the viral polymerase, the glucocorticosteroide Dexamethasone as well as neutralizing antibodies. The therapeutic benefits of these treatments are under ongoing debate and clinical studies assessing the efficiency of these treatments are still underway. To identify new therapeutic treatments for COVID-19, now and by the post-pandemic era, diverse experimental approaches are under scientific evaluation in companies and scientific research teams all over the world. To accelerate clinical translation of promising candidates, repurposing approaches of known approved drugs are specifically fostered but also novel technologies are being developed and are under investigation. This review summarizes the recent developments from the lab bench as well as the clinical status of emerging therapeutic candidates and discusses possible therapeutic entry points for the treatment strategies with regard to the biology of SARS-CoV-2 and the clinical course of COVID-19.
Collapse
Affiliation(s)
- Sriram Kumar
- Institute of Virology, University of Münster, Münster, Germany
- EvoPAD Research Training Group 2220, University of Münster, Münster, Germany
| | - Duygu Merve Çalışkan
- Institute of Virology, University of Münster, Münster, Germany
- EvoPAD Research Training Group 2220, University of Münster, Münster, Germany
| | - Josua Janowski
- Institute of Virology, University of Münster, Münster, Germany
- SP BioSciences Graduate Program, University of Münster, Münster, Germany
| | - Aileen Faist
- Institute of Virology, University of Münster, Münster, Germany
- CiM-IMPRS Graduate Program, University of Münster, Münster, Germany
| | | | - Julius Lange
- Institute of Virology, University of Münster, Münster, Germany
| | - Stephan Ludwig
- Institute of Virology, University of Münster, Münster, Germany
- EvoPAD Research Training Group 2220, University of Münster, Münster, Germany
- CiM-IMPRS Graduate Program, University of Münster, Münster, Germany
- Interdisciplinary Centre for Medical Research, University of Münster, Münster, Germany
| | - Linda Brunotte
- Institute of Virology, University of Münster, Münster, Germany
- Interdisciplinary Centre for Medical Research, University of Münster, Münster, Germany
| |
Collapse
|
43
|
Mamun AA, Akter F, Khan M, Ahmed SS, Uddin MG, Tasfia NT, Efaz FM, Ali MA, Sultana MUC, Halim MA. Identification of potent inhibitors against transmembrane serine protease 2 for developing therapeutics against SARS-CoV-2. J Biomol Struct Dyn 2021; 40:13049-13061. [PMID: 34590967 PMCID: PMC8500310 DOI: 10.1080/07391102.2021.1980109] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/24/2021] [Accepted: 09/08/2021] [Indexed: 12/27/2022]
Abstract
In viral binding and entry, the Spike(S) protein of SARS-CoV-2 uses transmembrane serine protease 2 (TMPRSS2) for priming to cleavage themselves. In this study, we have screened 'drug-like' 7476 ligands and found that over thirty ligands can effectively inhibit the TMPRSS-2 better than the control ligand. Finally, the three best drug agents L1, L2, and L6 were selected according to their average binding affinities and fitting score. These ligands interact with Asp435, Cys437, Ser436, Trp461, and Cys465 amino acid residues. The three best candidates and a reported drug Nafamostat mesylate (NAM) were selected to run 250 ns molecular dynamics (MD) simulations. Various properties of ligand-protein interactions obtained from MD simulation such as bonds, angle, dihedral, planarity, coulomb, and van der Waals (VdW) were used for principal component analysis (PCA) calculation. PCA discloses the evidence of the structural similarities to the corresponding complexes of L1, L2, and L6 with the complex of TMPRSS2(TM) and Nafamostat mesylate (TM-NAM). Moreover, Quantitative structure-activity relationship (QSAR) pattern recognition was generated using PCA for the investigation of structural similarities among the selected ligands. Multiple Linear Regression (MLR) model was built to predict the binding energy compared to the binding energy obtained from molecular docking. The MLR regression model reveals an accuracy of 80% for the prediction of the binding energy of ligands. ADMET analysis demonstrates that these drug agents are appeared to be safer inhibitors. These three ligands can be used as potential inhibitors against the TMPRSS2.Communicated by Ramaswamy H. Sarma.
Collapse
Affiliation(s)
- Abdulla Al Mamun
- Division of Infectious Diseases and Division of Computer Aided Drug Design, The Red-Green Research Centre, Dhaka, Bangladesh
- Key Laboratory of Soft Chemistry and Functional Materials of MOE, School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing, P. R. China
| | - Farjana Akter
- Division of Infectious Diseases and Division of Computer Aided Drug Design, The Red-Green Research Centre, Dhaka, Bangladesh
| | - Maksud Khan
- Division of Infectious Diseases and Division of Computer Aided Drug Design, The Red-Green Research Centre, Dhaka, Bangladesh
| | - Sayeda Samina Ahmed
- Division of Infectious Diseases and Division of Computer Aided Drug Design, The Red-Green Research Centre, Dhaka, Bangladesh
| | - Md. Giash Uddin
- Division of Infectious Diseases and Division of Computer Aided Drug Design, The Red-Green Research Centre, Dhaka, Bangladesh
- Department of Pharmacy, University of Chittagong, Chittagong, Bangladesh
| | - Nabila Tabassum Tasfia
- Division of Infectious Diseases and Division of Computer Aided Drug Design, The Red-Green Research Centre, Dhaka, Bangladesh
| | - Faiyaz Md. Efaz
- Division of Infectious Diseases and Division of Computer Aided Drug Design, The Red-Green Research Centre, Dhaka, Bangladesh
| | - Md Ackas Ali
- Division of Infectious Diseases and Division of Computer Aided Drug Design, The Red-Green Research Centre, Dhaka, Bangladesh
| | - Mossammad Umme Chand Sultana
- Division of Infectious Diseases and Division of Computer Aided Drug Design, The Red-Green Research Centre, Dhaka, Bangladesh
| | - Mohammad A. Halim
- Department of Chemistry and Biochemistry, Kennesaw State University, Kennesaw, GA, USA
| |
Collapse
|
44
|
Krüger N, Rocha C, Runft S, Krüger J, Färber I, Armando F, Leitzen E, Brogden G, Gerold G, Pöhlmann S, Hoffmann M, Baumgärtner W. The Upper Respiratory Tract of Felids Is Highly Susceptible to SARS-CoV-2 Infection. Int J Mol Sci 2021; 22:10636. [PMID: 34638978 PMCID: PMC8508926 DOI: 10.3390/ijms221910636] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/04/2021] [Revised: 09/24/2021] [Accepted: 09/28/2021] [Indexed: 02/07/2023] Open
Abstract
Natural or experimental infection of domestic cats and virus transmission from humans to captive predatory cats suggest that felids are highly susceptible to SARS-CoV-2 infection. However, it is unclear which cells and compartments of the respiratory tract are infected. To address this question, primary cell cultures derived from the nose, trachea, and lungs of cat and lion were inoculated with SARS-CoV-2. Strong viral replication was observed for nasal mucosa explants and tracheal air-liquid interface cultures, whereas replication in lung slices was less efficient. Infection was mainly restricted to epithelial cells and did not cause major pathological changes. Detection of high ACE2 levels in the nose and trachea but not lung further suggests that susceptibility of feline tissues to SARS-CoV-2 correlates with ACE2 expression. Collectively, this study demonstrates that SARS-CoV-2 can efficiently replicate in the feline upper respiratory tract ex vivo and thus highlights the risk of SARS-CoV-2 spillover from humans to felids.
Collapse
Affiliation(s)
- Nadine Krüger
- Infection Biology Unit, German Primate Center, 37077 Göttingen, Germany; (C.R.); (S.P.); (M.H.)
| | - Cheila Rocha
- Infection Biology Unit, German Primate Center, 37077 Göttingen, Germany; (C.R.); (S.P.); (M.H.)
| | - Sandra Runft
- Department of Pathology, University of Veterinary Medicine, Foundation, 30559 Hannover, Germany; (S.R.); (J.K.); (I.F.); (F.A.); (E.L.); (W.B.)
| | - Johannes Krüger
- Department of Pathology, University of Veterinary Medicine, Foundation, 30559 Hannover, Germany; (S.R.); (J.K.); (I.F.); (F.A.); (E.L.); (W.B.)
| | - Iris Färber
- Department of Pathology, University of Veterinary Medicine, Foundation, 30559 Hannover, Germany; (S.R.); (J.K.); (I.F.); (F.A.); (E.L.); (W.B.)
| | - Federico Armando
- Department of Pathology, University of Veterinary Medicine, Foundation, 30559 Hannover, Germany; (S.R.); (J.K.); (I.F.); (F.A.); (E.L.); (W.B.)
| | - Eva Leitzen
- Department of Pathology, University of Veterinary Medicine, Foundation, 30559 Hannover, Germany; (S.R.); (J.K.); (I.F.); (F.A.); (E.L.); (W.B.)
| | - Graham Brogden
- Department of Biochemistry, University of Veterinary Medicine, Foundation, 30559 Hannover, Germany; (G.B.); (G.G.)
- Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine, Foundation, 30559 Hannover, Germany
- Institute of Experimental Virology, TWINCORE, Center for Experimental and Clinical Infection Research Hannover, 30625 Hannover, Germany
| | - Gisa Gerold
- Department of Biochemistry, University of Veterinary Medicine, Foundation, 30559 Hannover, Germany; (G.B.); (G.G.)
- Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine, Foundation, 30559 Hannover, Germany
- Institute of Experimental Virology, TWINCORE, Center for Experimental and Clinical Infection Research Hannover, 30625 Hannover, Germany
- Wallenberg Centre for Molecular Medicine (WCMM), Umeå University, 90185 Umeå, Sweden
- Department of Clinical Microbiology, Umeå University, 90185 Umeå, Sweden
| | - Stefan Pöhlmann
- Infection Biology Unit, German Primate Center, 37077 Göttingen, Germany; (C.R.); (S.P.); (M.H.)
- Faculty of Biology and Psychology, Georg-August-University, 37073 Göttingen, Germany
| | - Markus Hoffmann
- Infection Biology Unit, German Primate Center, 37077 Göttingen, Germany; (C.R.); (S.P.); (M.H.)
- Faculty of Biology and Psychology, Georg-August-University, 37073 Göttingen, Germany
| | - Wolfgang Baumgärtner
- Department of Pathology, University of Veterinary Medicine, Foundation, 30559 Hannover, Germany; (S.R.); (J.K.); (I.F.); (F.A.); (E.L.); (W.B.)
| |
Collapse
|
45
|
Martin G, Wolf J, Lapp T, Agostini HT, Schlunck G, Auw-Hädrich C, Lange CAK. Viral S protein histochemistry reveals few potential SARS-CoV-2 entry sites in human ocular tissues. Sci Rep 2021; 11:19140. [PMID: 34580409 PMCID: PMC8476534 DOI: 10.1038/s41598-021-98709-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/29/2021] [Accepted: 09/13/2021] [Indexed: 12/17/2022] Open
Abstract
Despite the reported low expression of the primary SARS-CoV-2 receptor ACE2 in distinct ocular tissues, some clinical evidence suggests that SARS-CoV-2 can infect the eye. In this study, we explored potential entry sites for SARS-CoV-2 by viral S protein histochemistry on various ocular tissues and compared the staining patterns with RNA and protein expression of TMPRSS2 and ACE2. Potential viral entry sites were investigated by histochemistry using tagged recombinant viral S protein on 52 ocular tissue samples including specimens of the cornea, conjunctiva, lid margin, lacrimal gland tissue, retina, choroid, and RPE. In addition, ACE2 and TMPRSS2 immunohistochemistry were performed on the same ocular tissue, each with distinct antibodies binding to different epitopes. Lung tissue samples were used as positive controls. Finally, bulk RNA sequencing (RNA-Seq) was used to determine the expression of ACE2 and its auxiliary factors in the tissues mentioned above. S protein histochemistry revealed a positive staining in lung tissue but absent staining in the cornea, the conjunctiva, eye lid samples, the lacrimal glands, the retina and the optic nerve which was supported by hardly any immunoreactivity for ACE2 and TMPRSS2 and scarce ACE2 and TMPRSS2 RNA expression. Negligible staining with antibodies targeting ACE2 or TMPRSS2 was seen in the main and accessory lacrimal glands. In contrast, ocular staining (S protein, ACE2, TMPRSS2) was distinctly present in pigmented cells of the RPE and choroid, as well as in the ciliary body and the iris stroma. S protein histochemistry revealed hardly any SARS-CoV-2 entry sites in all ocular tissues examined. Similarly, no significant ACE2 or TMPRSS2 expression was found in extra- and intraocular tissue. While this study suggest a rather low risk of ocular infection with SARS-CoV-2, it should be noted, that potential viral entry sites may increase in response to inflammation or in certain disease states.
Collapse
Affiliation(s)
- Gottfried Martin
- Eye Center, Medical Center, Medical Faculty, University of Freiburg, Killianstr. 5, 79106, Freiburg, Germany.
| | - Julian Wolf
- Eye Center, Medical Center, Medical Faculty, University of Freiburg, Killianstr. 5, 79106, Freiburg, Germany
| | - Thabo Lapp
- Eye Center, Medical Center, Medical Faculty, University of Freiburg, Killianstr. 5, 79106, Freiburg, Germany
| | - Hansjürgen T Agostini
- Eye Center, Medical Center, Medical Faculty, University of Freiburg, Killianstr. 5, 79106, Freiburg, Germany
| | - Günther Schlunck
- Eye Center, Medical Center, Medical Faculty, University of Freiburg, Killianstr. 5, 79106, Freiburg, Germany
| | - Claudia Auw-Hädrich
- Eye Center, Medical Center, Medical Faculty, University of Freiburg, Killianstr. 5, 79106, Freiburg, Germany
| | - Clemens A K Lange
- Eye Center, Medical Center, Medical Faculty, University of Freiburg, Killianstr. 5, 79106, Freiburg, Germany.
| |
Collapse
|
46
|
Ensor CM, AlSiraj Y, Shoemaker R, Sturgill J, Keshavamurthy S, Gordon EM, Dong BE, Waters C, Cassis LA. SARS-CoV-2 Spike Protein Regulation of Angiotensin Converting Enzyme 2 and Tissue Renin-Angiotensin Systems: Influence of Biologic Sex. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2021:2021.09.14.460275. [PMID: 34545369 PMCID: PMC8452098 DOI: 10.1101/2021.09.14.460275] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Indexed: 11/24/2022]
Abstract
Angiotensin converting enzyme 2 (ACE2) is an enzyme that limits activity of the renin-angiotensin system (RAS) and also serves as a receptor for the SARS-CoV-2 Spike (S) protein. Binding of S protein to ACE2 causes internalization which activates local RAS. ACE2 is on the X chromosome and its expression is regulated by sex hormones. In this study, we defined ACE2 mRNA abundance and examined effects of S protein on ACE2 activity and/or angiotensin II (AngII) levels in pivotal tissues (lung, adipose) from male and female mice. In lung, ACE2 mRNA abundance was reduced following gonadectomy (GDX) of male and female mice and was higher in XX than XY mice of the Four Core Genotypes (FCG). Reductions in lung ACE2 mRNA abundance by GDX occurred in XX, but not XY FCG female mice. Lung mRNA abundance of ADAM17 and TMPRSS2, enzymes that shed cell surface ACE2 and facilitate viral cell entry, was reduced by GDX in male but not female mice. For comparison, adipose ACE2 mRNA abundance was higher in female than male mice and higher in XX than XY FCG mice. Adipose ADAM17 mRNA abundance was increased by GDX of male and female mice. S protein reduced ACE2 activity in alveolar type II epithelial cells and 3T3-L1 adipocytes. Administration of S protein to male and female mice increased lung AngII levels and decreased adipose ACE2 activity in male but not female mice. These results demonstrate that sex differences in ACE2 expression levels may impact local RAS following S protein exposures.
Collapse
Affiliation(s)
- Charles M Ensor
- Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536
| | - Yasir AlSiraj
- Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536
| | - Robin Shoemaker
- Department of Dietetics and Human Nutrition, College of Food, Agriculture and the Environment, University of Kentucky, Lexington, KY 40536
| | - Jamie Sturgill
- Department of Internal Medicine, College of Medicine, University of Kentucky, Lexington, KY 40536
| | - Suresh Keshavamurthy
- Division of Cardiothoracic Surgery, Department of Surgery, College of Medicine, University of Kentucky, Lexington, KY 40536
| | - Elizabeth M Gordon
- Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536
| | - Brittany E Dong
- Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536
| | - Christopher Waters
- Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536
| | - Lisa A Cassis
- Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536
| |
Collapse
|
47
|
Unravelling the Phytochemical Composition and the Pharmacological Properties of an Optimized Extract from the Fruit from Prunus mahaleb L.: From Traditional Liqueur Market to the Pharmacy Shelf. Molecules 2021; 26:molecules26154422. [PMID: 34361576 PMCID: PMC8347645 DOI: 10.3390/molecules26154422] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/29/2021] [Revised: 07/15/2021] [Accepted: 07/15/2021] [Indexed: 12/15/2022] Open
Abstract
Prunus mahaleb L. fruit has long been used in the production of traditional liqueurs. The fruit also displayed scavenging and reducing activity, in vitro. The present study focused on unravelling peripheral and central protective effects, antimicrobial but also anti-COVID-19 properties exerted by the water extract of P. mahaleb. Anti-inflammatory effects were studied in isolated mouse colons exposed to lipopolysaccharide. Neuroprotection, measured as a blunting effect on hydrogen-peroxide-induced dopamine turnover, was investigated in hypothalamic HypoE22 cells. Antimicrobial effects were tested against different Gram+ and Gram- bacterial strains. Whereas anti-COVID-19 activity was studied in lung adenocarcinoma H1299 cells, where the gene expression of ACE2 and TMPRSS2 was measured after extract treatment. The bacteriostatic effects induced on Gram+ and Gram- strains, together with the inhibition of COX-2, TNFα, HIF1α, and VEGFA in the colon, suggest the potential of P. mahaleb water extract in contrasting the clinical symptoms related to ulcerative colitis. The inhibition of the hydrogen peroxide-induced DOPAC/DA ratio indicates promising neuroprotective effects. Finally, the downregulation of the gene expression of ACE2 and TMPRSS2 in H1299 cells, suggests the potential to inhibit SARS-CoV-2 virus entry in the human host. Overall, the results support the valorization of the local cultivation of P. mahaleb.
Collapse
|
48
|
Giraldo-Ramirez S, Rendon-Marin S, Jaimes JA, Martinez-Gutierrez M, Ruiz-Saenz J. SARS-CoV-2 Clinical Outcome in Domestic and Wild Cats: A Systematic Review. Animals (Basel) 2021; 11:2056. [PMID: 34359182 PMCID: PMC8300124 DOI: 10.3390/ani11072056] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/03/2021] [Revised: 06/21/2021] [Accepted: 06/23/2021] [Indexed: 12/13/2022] Open
Abstract
Recently, it has been proved that SARS-CoV-2 has the ability to infect multiple species. This work was aimed at identifying the clinical signs of SARS-CoV-2 infection in domestic and wild felids. A PRISMA-based systematic review was performed on case reports on domestic and wild cats, reports on experimental infections, case reports in databases, preprints and published press releases. Descriptive statistical analysis of the data was performed. A total of 256 articles, 63 detailed official reports and 2 press articles on SARS-CoV-2 infection in domestic and wild cats were analyzed, of which 19 articles and 65 reports were finally included. In domestic cats, most cats' infections are likely to be asymptomatic, and 46% of the reported infected animals were symptomatic and predominantly presented respiratory signs such as sneezing and coughing. In wild felines, respiratory clinical signs were most frequent, and up to 96.5% of the reported affected animals presented coughing. It is noteworthy that, to date, symptomatic animals with SARS-CoV-2 infection have been reported to belong to two different subfamilies (Phanterinae and Felinae), with up to five different felid species affected within the Felidae family. Reported results evince that the signs developed in felids show similar progression to those occurring in humans, suggesting a relationship between the viral cycle and target tissues of the virus in different species. While viral transmission to humans in contact with animal populations has not been reported, spill-back could result in the emergence of immune-escape mutants that might pose a risk to public health. Despite the clear results in the identification of the typical clinical picture of SARS-CoV-2 infection in felines, the number of detailed academic reports and papers on the subject is scarce. Therefore, further description of these cases will allow for more accurate and statistically robust clinical approaches in the future.
Collapse
Affiliation(s)
- Sebastian Giraldo-Ramirez
- Grupo de Investigación en Ciencias Animales—GRICA, Facultad de Medicina Veterinaria y Zootecnia, Universidad Cooperativa de Colombia, Bucaramanga 680002, Colombia; (S.G.-R.); (S.R.-M.); (M.M.-G.)
| | - Santiago Rendon-Marin
- Grupo de Investigación en Ciencias Animales—GRICA, Facultad de Medicina Veterinaria y Zootecnia, Universidad Cooperativa de Colombia, Bucaramanga 680002, Colombia; (S.G.-R.); (S.R.-M.); (M.M.-G.)
| | - Javier A. Jaimes
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA;
| | - Marlen Martinez-Gutierrez
- Grupo de Investigación en Ciencias Animales—GRICA, Facultad de Medicina Veterinaria y Zootecnia, Universidad Cooperativa de Colombia, Bucaramanga 680002, Colombia; (S.G.-R.); (S.R.-M.); (M.M.-G.)
- Infettare, Facultad de Medicina, Universidad Cooperativa de Colombia, Medellín 050012, Colombia
| | - Julian Ruiz-Saenz
- Grupo de Investigación en Ciencias Animales—GRICA, Facultad de Medicina Veterinaria y Zootecnia, Universidad Cooperativa de Colombia, Bucaramanga 680002, Colombia; (S.G.-R.); (S.R.-M.); (M.M.-G.)
| |
Collapse
|
49
|
Vianello A, Del Turco S, Babboni S, Silvestrini B, Ragusa R, Caselli C, Melani L, Fanucci L, Basta G. The Fight against COVID-19 on the Multi-Protease Front and Surroundings: Could an Early Therapeutic Approach with Repositioning Drugs Prevent the Disease Severity? Biomedicines 2021; 9:710. [PMID: 34201505 PMCID: PMC8301470 DOI: 10.3390/biomedicines9070710] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/24/2021] [Revised: 06/17/2021] [Accepted: 06/17/2021] [Indexed: 12/15/2022] Open
Abstract
The interaction between the membrane spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the transmembrane angiotensin-converting enzyme 2 (ACE2) receptor of the human epithelial host cell is the first step of infection, which has a critical role for viral pathogenesis of the current coronavirus disease-2019 (COVID-19) pandemic. Following the binding between S1 subunit and ACE2 receptor, different serine proteases, including TMPRSS2 and furin, trigger and participate in the fusion of the viral envelope with the host cell membrane. On the basis of the high virulence and pathogenicity of SARS-CoV-2, other receptors have been found involved for viral binding and invasiveness of host cells. This review comprehensively discusses the mechanisms underlying the binding of SARS-CoV2 to ACE2 and putative alternative receptors, and the role of potential co-receptors and proteases in the early stages of SARS-CoV-2 infection. Given the short therapeutic time window within which to act to avoid the devastating evolution of the disease, we focused on potential therapeutic treatments-selected mainly among repurposing drugs-able to counteract the invasive front of proteases and mild inflammatory conditions, in order to prevent severe infection. Using existing approved drugs has the advantage of rapidly proceeding to clinical trials, low cost and, consequently, immediate and worldwide availability.
Collapse
Affiliation(s)
- Annamaria Vianello
- Department of Information Engineering, Telemedicine Section, University of Pisa, 56122 Pisa, Italy; (A.V.); (L.F.)
| | - Serena Del Turco
- Council of National Research (CNR), Institute of Clinical Physiology, 56124 Pisa, Italy; (S.B.); (R.R.); (C.C.)
| | - Serena Babboni
- Council of National Research (CNR), Institute of Clinical Physiology, 56124 Pisa, Italy; (S.B.); (R.R.); (C.C.)
| | - Beatrice Silvestrini
- Department of Surgical, Medical, Molecular Pathology, and Critical Area, University of Pisa, 56122 Pisa, Italy;
| | - Rosetta Ragusa
- Council of National Research (CNR), Institute of Clinical Physiology, 56124 Pisa, Italy; (S.B.); (R.R.); (C.C.)
| | - Chiara Caselli
- Council of National Research (CNR), Institute of Clinical Physiology, 56124 Pisa, Italy; (S.B.); (R.R.); (C.C.)
| | - Luca Melani
- Department of Territorial Medicine, ASL Toscana Nord-Ovest, 56121 Pisa, Italy;
| | - Luca Fanucci
- Department of Information Engineering, Telemedicine Section, University of Pisa, 56122 Pisa, Italy; (A.V.); (L.F.)
| | - Giuseppina Basta
- Council of National Research (CNR), Institute of Clinical Physiology, 56124 Pisa, Italy; (S.B.); (R.R.); (C.C.)
| |
Collapse
|
50
|
Megyeri K, Dernovics Á, Al-Luhaibi ZII, Rosztóczy A. COVID-19-associated diarrhea. World J Gastroenterol 2021; 27:3208-3222. [PMID: 34163106 PMCID: PMC8218355 DOI: 10.3748/wjg.v27.i23.3208] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 01/28/2021] [Revised: 03/19/2021] [Accepted: 05/20/2021] [Indexed: 02/06/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently emerged as a highly virulent respiratory pathogen that is known as the causative agent of coronavirus disease 2019 (COVID-19). Diarrhea is a common early symptom in a significant proportion of patients with SARS-CoV-2 infection. SARS-CoV-2 can infect and replicate in esophageal cells and enterocytes, leading to direct damage to the intestinal epithelium. The infection decreases the level of angiotensin-converting enzyme 2 receptors, thereby altering the composition of the gut microbiota. SARS-CoV-2 elicits a cytokine storm, which contributes to gastrointestinal inflammation. The direct cytopathic effects of SARS-CoV-2, gut dysbiosis, and aberrant immune response result in increased intestinal permeability, which may exacerbate existing symptoms and worsen the prognosis. By exploring the elements of pathogenesis, several therapeutic options have emerged for the treatment of COVID-19 patients, such as biologics and biotherapeutic agents. However, the presence of SARS-CoV-2 in the feces may facilitate the spread of COVID-19 through fecal-oral transmission and contaminate the environment. Thus gastrointestinal SARS-CoV-2 infection has important epidemiological significance. The development of new therapeutic and preventive options is necessary to treat and restrict the spread of this severe and widespread infection more effectively. Therefore, we summarize the key elements involved in the pathogenesis and the epidemiology of COVID-19-associated diarrhea.
Collapse
Affiliation(s)
- Klara Megyeri
- Department of Medical Microbiology and Immunobiology, University of Szeged, Szeged 6720, Csongrad, Hungary
| | - Áron Dernovics
- Department of Medical Microbiology and Immunobiology, University of Szeged, Szeged 6720, Csongrad, Hungary
| | - Zaid I I Al-Luhaibi
- Department of Medical Microbiology and Immunobiology, University of Szeged, Szeged 6720, Csongrad, Hungary
| | - András Rosztóczy
- Division of Gastroenterology, Department of Internal Medicine, University of Szeged, Szeged 6720, Csongrad, Hungary
| |
Collapse
|