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Aw DZH, Zhang DX, Vignuzzi M. Strategies and efforts in circumventing the emergence of antiviral resistance against conventional antivirals. NPJ ANTIMICROBIALS AND RESISTANCE 2025; 3:54. [PMID: 40490516 DOI: 10.1038/s44259-025-00125-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 05/21/2025] [Indexed: 06/11/2025]
Abstract
Antiviral resistance stemming from rapid viral evolution and adaptation is a major challenge faced in treating viral infections. Here, we describe the mechanisms and factors underlying antiviral resistance and their implications to future drug development. Current improvements to conventional methods provide viable options to overcome antiviral resistance. Ongoing efforts in developing new antiviral strategies are also discussed. Examples from across virology are used to illustrate how virus evolution and antiviral therapy influence each other.
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Affiliation(s)
- Daryl Zheng Hao Aw
- A*STAR Infectious Diseases Labs (A*STAR ID Labs), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos #05-13, Singapore, 138648, Singapore
| | - Denzel Xugeng Zhang
- A*STAR Infectious Diseases Labs (A*STAR ID Labs), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos #05-13, Singapore, 138648, Singapore
| | - Marco Vignuzzi
- A*STAR Infectious Diseases Labs (A*STAR ID Labs), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos #05-13, Singapore, 138648, Singapore.
- Infectious Diseases Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
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2
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Kulakova L, Li KH, Chiang AWT, Schwoerer MP, Schoffelen S, Elkholy K, Chao KL, Shahid S, Kumar B, Murray NB, Archer-Hartmann S, Azadi P, Voldborg BG, Marin A, Mariuzza RA, Andrianov AK, Ploss A, Lewis NE, Toth EA, Fuerst TR. Glycoengineering of the hepatitis C virus E2 glycoprotein leads to improved biochemical properties and enhanced immunogenicity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.04.02.646860. [PMID: 40291659 PMCID: PMC12026506 DOI: 10.1101/2025.04.02.646860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
An effective vaccine against hepatitis C virus (HCV) must elicit the production of broadly neutralizing antibodies (bnAbs) reproducibly against the E1E2 glycoprotein complex. Little is known about how glycan content affects this process. Ideally, glycans would maximize epitope exposure without compromising antigen stability or exposing new epitopes. However, typical recombinant vaccines contain considerable heterogeneity in glycan content, which can affect the antibody response and neutralization potency. Here we employed glycoengineered Chinese hamster ovary (geCHO) cell lines that impart nearly homogeneous glycosylation as a means to test how specific glycan features influence antigenicity and immunogenicity for the secreted HCV E2 ectodomain (sE2). Specific geCHO antigens exhibited a modest but reproducible increase in affinity for some mAbs relative to CHO- and HEK293-produced sE2. Surprisingly, one geCHO sE2 antigen failed to bind the CD81 receptor, indicating the potential for significant glycan effects on biochemical properties. We immunized mice with the four antigens and found the total antibody response to be the same for all groups. However, sera from one geCHO group exhibited a 7-fold improvement in neutralization against the homologous HCV pseudovirus and had the most mice whose sera exhibited neutralization activity against genotypes 1b, 2a, 2b, and 3. Further analysis identified beneficial and deleterious glycan features, and the glycan that correlated the most with decreased potency was relatively small. However, size was not the sole determinant of glycan-driven effects on the antibody response. In summary, glycan content impacts biochemical properties of antigens to varying degrees and such effects can influence immune response quality and uniformity.
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3
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Goonawardane N, Yin C, Roberts GC, Zothner C, Harris M. A key role for hepatitis C virus NS5A serine 225 phosphorylation revealed by super-resolution microscopy. Sci Rep 2025; 15:9567. [PMID: 40113977 PMCID: PMC11926191 DOI: 10.1038/s41598-025-93812-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 03/10/2025] [Indexed: 03/22/2025] Open
Abstract
NS5A is a multi-functional phosphoprotein that plays a key role in hepatitis C virus (HCV) genome replication and assembly. The consequences of NS5A phosphorylation for HCV biology remain largely undefined. We previously identified serine 225 (S225) as a major phosphorylation site within the low complexity sequence 1 (LCSI) of NS5A and used a phosphoablatant mutant (S225A) to define the role of this phosphorylation event in genome replication, NS5A-host interactions and sub-cellular localisation. In this study, we investigate this further by raising an antiserum to S225 phosphorylated NS5A (pS225). Western blot analysis revealed that pS225 was predominantly in the hyper-phosphorylated NS5A species. Using a panel of phosphoablatant mutants of other phosphorylation sites in LCSI, we obtained evidence that is consistent with bidirectional hierarchical phosphorylation initiated by phosphorylation at S225. Using super-resolution microscopy (Airyscan and Expansion), we revealed a unique architecture of NS5A-positive punctae in HCV-infected cells; pS225 was present on the surface of these punctae, close to lipid droplets. Although S225 phosphorylation was not specifically affected by treatment with the NS5A-targeting direct acting antiviral agent daclatasvir, this resulted in the condensation of NS5A-positive punctae into larger structures, recapitulating the S225A phenotype. These data are consistent with a key role for S225 phosphorylation in the regulation of NS5A function.
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Affiliation(s)
- Niluka Goonawardane
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - Chunhong Yin
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
- Infectious Disease Control Institute, Shandong Center for Disease Control and Prevention, Shandong Provincial Key Laboratory of Infectious Disease Prevention and Control, Jinan, 250014, Shandong, People's Republic of China
| | - Grace C Roberts
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - Carsten Zothner
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - Mark Harris
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK.
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4
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Aoki-Utsubo C, Kameoka M, Deng L, Hanafi M, Dewi BE, Sudarmono P, Wakita T, Hotta H. Statins enhance extracellular release of hepatitis C virus particles through ERK5 activation. Microbiol Immunol 2024; 68:359-370. [PMID: 39073705 DOI: 10.1111/1348-0421.13166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 06/13/2024] [Accepted: 07/09/2024] [Indexed: 07/30/2024]
Abstract
Statins, such as lovastatin, have been known to inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Statins were reported to moderately suppress hepatitis C virus (HCV) replication in cultured cells harboring HCV RNA replicons. We report here using an HCV cell culture (HCVcc) system that high concentrations of lovastatin (5-20 μg/mL) markedly enhanced the release of HCV infectious particles (virion) in the culture supernatants by up to 40 times, without enhancing HCV RNA replication, HCV protein synthesis, or HCV virion assembly in the cells. We also found that lovastatin increased the phosphorylation (activation) level of extracellular-signal-regulated kinase 5 (ERK5) in both the infected and uninfected cells in a dose-dependent manner. The lovastatin-mediated increase of HCV virion release was partially reversed by selective ERK5 inhibitors, BIX02189 and XMD8-92, or by ERK5 knockdown using small interfering RNA (siRNA). Moreover, we demonstrated that other cholesterol-lowering statins, but not dehydrolovastatin that is incapable of inhibiting HMG-CoA reductase and activating ERK5, enhanced HCV virion release to the same extent as observed with lovastatin. These results collectively suggest that statins markedly enhance HCV virion release from infected cells through HMG-CoA reductase inhibition and ERK5 activation.
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Affiliation(s)
- Chie Aoki-Utsubo
- Department of Public Health, Graduate School of Health Sciences, Kobe University, Kobe, Japan
| | - Masanori Kameoka
- Department of Public Health, Graduate School of Health Sciences, Kobe University, Kobe, Japan
| | - Lin Deng
- Division of Infectious Disease Control, Graduate School of Medicine, Kobe University, Kobe, Japan
| | - Muhammad Hanafi
- Research Center for Chemistry, National Research and Innovation Agency (BRIN), Serpong, Indonesia
| | - Beti Ernawati Dewi
- Department of Microbiology, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
| | - Pratiwi Sudarmono
- Department of Microbiology, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
| | - Takaji Wakita
- National Institute of Infectious Diseases, Tokyo, Japan
| | - Hak Hotta
- Department of Public Health, Graduate School of Health Sciences, Kobe University, Kobe, Japan
- Faculty of Clinical Nutrition and Dietetics, Konan Women's University, Kobe, Japan
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5
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Valente LC, Bacil GP, Riechelmann-Casarin L, Barbosa GC, Barbisan LF, Romualdo GR. Exploring in vitro modeling in hepatocarcinogenesis research: morphological and molecular features and similarities to the corresponding human disease. Life Sci 2024; 351:122781. [PMID: 38848937 DOI: 10.1016/j.lfs.2024.122781] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 04/04/2024] [Accepted: 06/04/2024] [Indexed: 06/09/2024]
Abstract
The hepatocellular carcinoma (HCC) features a remarkable epidemiological burden, ranking as the third most lethal cancer worldwide. As the HCC-related molecular and cellular complexity unfolds as the disease progresses, the use of a myriad of in vitro models available is mandatory in translational preclinical research setups. In this review paper, we will compile cutting-edge information on the in vitro bioassays for HCC research, (A) emphasizing their morphological and molecular parallels with human HCC; (B) delineating the advantages and limitations of their application; and (C) offering perspectives on their prospective applications. While bidimensional (2D) (co) culture setups provide a rapid low-cost strategy for metabolism and drug screening investigations, tridimensional (3D) (co) culture bioassays - including patient-derived protocols as organoids and precision cut slices - surpass some of the 2D strategies limitations, mimicking the complex microarchitecture and cellular and non-cellular microenvironment observed in human HCC. 3D models have become invaluable tools to unveil HCC pathophysiology and targeted therapy. In both setups, the recapitulation of HCC in different etiologies/backgrounds (i.e., viral, fibrosis, and fatty liver) may be considered as a fundamental guide for obtaining translational findings. Therefore, a "multimodel" approach - encompassing the advantages of different in vitro bioassays - is encouraged to circumvent "model-biased" outcomes in preclinical HCC research.
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Affiliation(s)
- Leticia Cardoso Valente
- São Paulo State University (UNESP), Medical School, Botucatu, Experimental Research Unit (UNIPEX), Brazil
| | - Gabriel Prata Bacil
- São Paulo State University (UNESP), Institute of Biosciences, Botucatu, Department of Structural and Functional Biology, Brazil
| | - Luana Riechelmann-Casarin
- São Paulo State University (UNESP), Medical School, Botucatu, Experimental Research Unit (UNIPEX), Brazil
| | | | - Luís Fernando Barbisan
- São Paulo State University (UNESP), Institute of Biosciences, Botucatu, Department of Structural and Functional Biology, Brazil
| | - Guilherme Ribeiro Romualdo
- São Paulo State University (UNESP), Medical School, Botucatu, Experimental Research Unit (UNIPEX), Brazil.
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6
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Iman K, Mirza MU, Sadia F, Froeyen M, Trant JF, Chaudhary SU. Pharmacophore-Assisted Covalent Docking Identifies a Potential Covalent Inhibitor for Drug-Resistant Genotype 3 Variants of Hepatitis C Viral NS3/4A Serine Protease. Viruses 2024; 16:1250. [PMID: 39205224 PMCID: PMC11359326 DOI: 10.3390/v16081250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Revised: 07/28/2024] [Accepted: 07/30/2024] [Indexed: 09/04/2024] Open
Abstract
The emergence of drug-resistance-inducing mutations in Hepatitis C virus (HCV) coupled with genotypic heterogeneity has made targeting NS3/4A serine protease difficult. In this work, we investigated the mutagenic variations in the binding pocket of Genotype 3 (G3) HCV NS3/4A and evaluated ligands for efficacious inhibition. We report mutations at 14 positions within the ligand-binding residues of HCV NS3/4A, including H57R and S139P within the catalytic triad. We then modelled each mutational variant for pharmacophore-based virtual screening (PBVS) followed by covalent docking towards identifying a potential covalent inhibitor, i.e., cpd-217. The binding stability of cpd-217 was then supported by molecular dynamic simulation followed by MM/GBSA binding free energy calculation. The free energy decomposition analysis indicated that the resistant mutants alter the HCV NS3/4A-ligand interaction, resulting in unbalanced energy distribution within the binding site, leading to drug resistance. Cpd-217 was identified as interacting with all NS3/4A G3 variants with significant covalent docking scores. In conclusion, cpd-217 emerges as a potential inhibitor of HCV NS3/4A G3 variants that warrants further in vitro and in vivo studies. This study provides a theoretical foundation for drug design and development targeting HCV G3 NS3/4A.
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Affiliation(s)
- Kanzal Iman
- Biomedical Informatics & Engineering Research Laboratory, Department of Life Sciences, Lahore University of Management Sciences, Lahore 36000, Pakistan; (K.I.); (F.S.)
| | - Muhammad Usman Mirza
- Department of Chemistry & Biochemistry, University of Windsor, Windsor, ON N9B 3P4, Canada;
| | - Fazila Sadia
- Biomedical Informatics & Engineering Research Laboratory, Department of Life Sciences, Lahore University of Management Sciences, Lahore 36000, Pakistan; (K.I.); (F.S.)
| | - Matheus Froeyen
- Department of Pharmaceutical and Pharmacological Sciences, Rega Institute for Medical Research, KU Leuven—University of Leuven, B-3000 Leuven, Belgium;
| | - John F. Trant
- Department of Chemistry & Biochemistry, University of Windsor, Windsor, ON N9B 3P4, Canada;
| | - Safee Ullah Chaudhary
- Biomedical Informatics & Engineering Research Laboratory, Department of Life Sciences, Lahore University of Management Sciences, Lahore 36000, Pakistan; (K.I.); (F.S.)
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7
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Sallam M, Khalil R. Contemporary Insights into Hepatitis C Virus: A Comprehensive Review. Microorganisms 2024; 12:1035. [PMID: 38930417 PMCID: PMC11205832 DOI: 10.3390/microorganisms12061035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 05/15/2024] [Accepted: 05/20/2024] [Indexed: 06/28/2024] Open
Abstract
Hepatitis C virus (HCV) remains a significant global health challenge. Approximately 50 million people were living with chronic hepatitis C based on the World Health Organization as of 2024, contributing extensively to global morbidity and mortality. The advent and approval of several direct-acting antiviral (DAA) regimens significantly improved HCV treatment, offering potentially high rates of cure for chronic hepatitis C. However, the promising aim of eventual HCV eradication remains challenging. Key challenges include the variability in DAA access across different regions, slightly variable response rates to DAAs across diverse patient populations and HCV genotypes/subtypes, and the emergence of resistance-associated substitutions (RASs), potentially conferring resistance to DAAs. Therefore, periodic reassessment of current HCV knowledge is needed. An up-to-date review on HCV is also necessitated based on the observed shifts in HCV epidemiological trends, continuous development and approval of therapeutic strategies, and changes in public health policies. Thus, the current comprehensive review aimed to integrate the latest knowledge on the epidemiology, pathophysiology, diagnostic approaches, treatment options and preventive strategies for HCV, with a particular focus on the current challenges associated with RASs and ongoing efforts in vaccine development. This review sought to provide healthcare professionals, researchers, and policymakers with the necessary insights to address the HCV burden more effectively. We aimed to highlight the progress made in managing and preventing HCV infection and to highlight the persistent barriers challenging the prevention of HCV infection. The overarching goal was to align with global health objectives towards reducing the burden of chronic hepatitis, aiming for its eventual elimination as a public health threat by 2030.
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Affiliation(s)
- Malik Sallam
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan
- Department of Clinical Laboratories and Forensic Medicine, Jordan University Hospital, Amman 11942, Jordan
| | - Roaa Khalil
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan
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Wang Q, Kline EC, Gilligan-Steinberg SD, Lai JJ, Hull IT, Olanrewaju AO, Panpradist N, Lutz BR. Sensitive Pathogen Detection and Drug Resistance Characterization Using Pathogen-Derived Enzyme Activity Amplified by LAMP or CRISPR-Cas. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.03.29.24305085. [PMID: 38633802 PMCID: PMC11023665 DOI: 10.1101/2024.03.29.24305085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/19/2024]
Abstract
Pathogens encapsulate or encode their own suite of enzymes to facilitate replication in the host. The pathogen-derived enzymes possess specialized activities that are essential for pathogen replication and have naturally been candidates for drug targets. Phenotypic assays detecting the activities of pathogen-derived enzymes and characterizing their inhibition under drugs offer an opportunity for pathogen detection, drug resistance testing for individual patients, and as a research tool for new drug development. Here, we used HIV as an example to develop assays targeting the reverse transcriptase (RT) enzyme encapsulated in HIV for sensitive detection and phenotypic characterization, with the potential for point-of-care (POC) applications. Specifically, we targeted the complementary (cDNA) generation activity of the HIV RT enzyme by adding engineered RNA as substrates for HIV RT enzyme to generate cDNA products, followed by cDNA amplification and detection facilitated by loop-mediated isothermal amplification (LAMP) or CRISPR-Cas systems. To guide the assay design, we first used qPCR to characterize the cDNA generation activity of HIV RT enzyme. In the LAMP-mediated Product-Amplified RT activity assay (LamPART), the cDNA generation and LAMP amplification were combined into one pot with novel assay designs. When coupled with direct immunocapture of HIV RT enzyme for sample preparation and endpoint lateral flow assays for detection, LamPART detected as few as 20 copies of HIV RT enzyme spiked into 25μL plasma (fingerstick volume), equivalent to a single virion. In the Cas-mediated Product-Amplified RT activity assay (CasPART), we tailored the substrate design to achieve a LoD of 2e4 copies (1.67fM) of HIV RT enzyme. Furthermore, with its phenotypic characterization capability, CasPART was used to characterize the inhibition of HIV RT enzyme under antiretroviral drugs and differentiate between wild-type and mutant HIV RT enzyme for potential phenotypic drug resistance testing. Moreover, the CasPART assay can be readily adapted to target the activity of other pathogen-derived enzymes. As a proof-of-concept, we successfully adapted CasPART to detect HIV integrase with a sensitivity of 83nM. We anticipate the developed approach of detecting enzyme activity with product amplification has the potential for a wide range of pathogen detection and phenotypic characterization.
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Affiliation(s)
- Qin Wang
- Department of Bioengineering, University of Washington, Seattle, WA, USA
| | - Enos C. Kline
- Department of Bioengineering, University of Washington, Seattle, WA, USA
| | | | - James J. Lai
- Department of Bioengineering, University of Washington, Seattle, WA, USA
- Department of Materials Science and Engineering, National Taiwan University of Science and Technology, Taipei, Taiwan
| | - Ian T. Hull
- Department of Bioengineering, University of Washington, Seattle, WA, USA
| | - Ayokunle O. Olanrewaju
- Department of Bioengineering, University of Washington, Seattle, WA, USA
- Department of Mechanical Engineering, University of Washington, Seattle, WA, USA
| | - Nuttada Panpradist
- Department of Bioengineering, University of Washington, Seattle, WA, USA
| | - Barry R. Lutz
- Department of Bioengineering, University of Washington, Seattle, WA, USA
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9
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Cooke GS. Viral Hepatitis. MANSON'S TROPICAL DISEASES 2024:152-166. [DOI: 10.1016/b978-0-7020-7959-7.00018-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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10
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Kamal S, Shahzad A, Rehman K, Tariq K, Akash MSH, Imran M, Assiri MA. Therapeutic Intervention of Serine Protease Inhibitors against Hepatitis C Virus. Curr Med Chem 2024; 31:2052-2072. [PMID: 37855348 DOI: 10.2174/0109298673234823230921090431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 05/12/2023] [Accepted: 05/23/2023] [Indexed: 10/20/2023]
Abstract
Hepatitis C virus (HCV) is a globally prevalent and hazardous disorder that is responsible for inducing several persistent and potentially fatal liver diseases. Current treatment strategies offer limited efficacy, often accompanied by severe and debilitating adverse effects. Consequently, there is an urgent and compelling need to develop novel therapeutic interventions that can provide maximum efficacy in combating HCV while minimizing the burden of adverse effects on patients. One promising target against HCV is the NS3-4A serine protease, a complex composed of two HCV-encoded proteins. This non-covalent heterodimer is crucial in the viral life cycle and has become a primary focus for therapeutic interventions. Although peginterferon, combined with ribavirin, is commonly employed for HCV treatment, its efficacy is hampered by significant adverse effects that can profoundly impact patients' quality of life. In recent years, the development of direct-acting antiviral agents (DAAs) has emerged as a breakthrough in HCV therapy. These agents exhibit remarkable potency against the virus and have demonstrated fewer adverse effects when combined with other DAAs. However, it is important to note that there is a potential for developing resistance to DAAs due to alterations in the amino acid position of the NS3-4A protease. This emphasizes the need for ongoing research to identify strategies that can minimize the emergence of resistance and ensure long-term effectiveness. While the combination of DAAs holds promise for HCV treatment, it is crucial to consider the possibility of drug-drug interactions. These interactions may occur when different DAAs are used concurrently, potentially compromising their therapeutic efficacy. Therefore, carefully evaluating and monitoring potential drug interactions are vital to optimize treatment outcomes. In the pursuit of novel therapeutic interventions for HCV, the field of computational biology and bioinformatics has emerged as a valuable tool. These advanced technologies and methodologies enable the development and design of new drugs and therapeutic agents that exhibit maximum efficacy, reduced risk of resistance, and minimal adverse effects. By leveraging computational approaches, researchers can efficiently screen and optimize potential candidates, accelerating the discovery and development of highly effective treatments for HCV, treatments.
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Affiliation(s)
- Shagufta Kamal
- Department of Biochemistry, Government College University, Faisalabad, Pakistan
| | - Asif Shahzad
- Department of Biochemistry, Government College University, Faisalabad, Pakistan
| | - Kanwal Rehman
- Department of Pharmacy, The Women University, Multan, Pakistan
| | - Komal Tariq
- Department of Biochemistry, Government College University, Faisalabad, Pakistan
| | | | - Muhammad Imran
- Research center for Advanced Materials Science (RCAMS), King Khalid University, Abha, Saudi Arabia
- Department of Chemistry, Faculty of Science, King Khalid University, Abha, Saudi Arabia
| | - Mohammed Ali Assiri
- Research center for Advanced Materials Science (RCAMS), King Khalid University, Abha, Saudi Arabia
- Department of Chemistry, Faculty of Science, King Khalid University, Abha, Saudi Arabia
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11
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Vincenzi M, Mercurio FA, Leone M. EPHA2 Receptor as a Possible Therapeutic Target in Viral Infections. Curr Med Chem 2024; 31:5670-5701. [PMID: 37828671 DOI: 10.2174/0109298673256638231003111234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 08/02/2023] [Accepted: 08/24/2023] [Indexed: 10/14/2023]
Abstract
BACKGROUND The receptor tyrosine kinase EphA2 plays a role in many diseases, like cancer, cataracts, and osteoporosis. Interestingly, it has also been linked to viral infections. OBJECTIVE Herein, current literature has been reviewed to clarify EphA2 functions in viral infections and explore its potential role as a target in antiviral drug discovery strategies. METHODS Research and review articles along with preprints connecting EphA2 to different viruses have been searched through PubMed and the web. Structures of complexes between EphA2 domains and viral proteins have been retrieved from the PDB database. RESULTS EphA2 assumes a key role in Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein Barr virus (EBV) infections by directly binding, through its ligand binding domain, viral glycoproteins. For human cytomegalovirus (HCMV), the role of EphA2 in maintaining virus latency state, through cooperation with specific viral proteins, has also been speculated. In certain cells, with high EphA2 expression levels, following ligand stimulation, receptor activation might contribute to severe symptoms accompanying a few viral infections, including lung injuries often related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). CONCLUSION Since EphA2 works as a host receptor for certain viruses, it might be worth more deeply investigating known compounds targeting its extracellular ligand binding domain as antiviral therapeutics. Due to EphA2's function in inflammation, its possible correlation with SARS-CoV-2 cannot be excluded, but more experimental studies are needed in this case to undoubtedly attribute the role of this receptor in viral infections.
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Affiliation(s)
- Marian Vincenzi
- Institute of Biostructures and Bioimaging, National Research Council of Italy (CNR-IBB), Naples, Italy
| | - Flavia Anna Mercurio
- Institute of Biostructures and Bioimaging, National Research Council of Italy (CNR-IBB), Naples, Italy
| | - Marilisa Leone
- Institute of Biostructures and Bioimaging, National Research Council of Italy (CNR-IBB), Naples, Italy
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12
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Deng L, Solichin MR, Adyaksa DNM, Septianastiti MA, Fitri RA, Suwardan GNR, Matsui C, Abe T, Shoji I. Cellular Release of Infectious Hepatitis C Virus Particles via Endosomal Pathways. Viruses 2023; 15:2430. [PMID: 38140670 PMCID: PMC10747773 DOI: 10.3390/v15122430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 12/07/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023] Open
Abstract
Hepatitis C virus (HCV) is a positive-sense, single-stranded RNA virus that causes chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. The release of infectious HCV particles from infected hepatocytes is a crucial step in viral dissemination and disease progression. While the exact mechanisms of HCV particle release remain poorly understood, emerging evidence suggests that HCV utilizes intracellular membrane trafficking and secretory pathways. These pathways include the Golgi secretory pathway and the endosomal trafficking pathways, such as the recycling endosome pathway and the endosomal sorting complex required for transport (ESCRT)-dependent multivesicular bodies (MVBs) pathway. This review provides an overview of recent advances in understanding the release of infectious HCV particles, with a particular focus on the involvement of the host cell factors that participate in HCV particle release. By summarizing the current knowledge in this area, this review aims to contribute to a better understanding of endosomal pathways involved in the extracellular release of HCV particles and the development of novel antiviral strategies.
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Affiliation(s)
- Lin Deng
- Division of Infectious Disease Control, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; (L.D.); (D.N.M.A.); (M.A.S.); (T.A.)
| | - Muchamad Ridotu Solichin
- Division of Infectious Disease Control, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; (L.D.); (D.N.M.A.); (M.A.S.); (T.A.)
- Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
| | - Dewa Nyoman Murti Adyaksa
- Division of Infectious Disease Control, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; (L.D.); (D.N.M.A.); (M.A.S.); (T.A.)
- Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
| | - Maria Alethea Septianastiti
- Division of Infectious Disease Control, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; (L.D.); (D.N.M.A.); (M.A.S.); (T.A.)
- Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
| | - Rhamadianti Aulia Fitri
- Division of Infectious Disease Control, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; (L.D.); (D.N.M.A.); (M.A.S.); (T.A.)
- Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
| | - Gede Ngurah Rsi Suwardan
- Division of Infectious Disease Control, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; (L.D.); (D.N.M.A.); (M.A.S.); (T.A.)
- Department of Clinical Microbiology, Faculty of Medicine, Universitas Udayana, Bali 80361, Indonesia
| | - Chieko Matsui
- Division of Infectious Disease Control, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; (L.D.); (D.N.M.A.); (M.A.S.); (T.A.)
| | - Takayuki Abe
- Division of Infectious Disease Control, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; (L.D.); (D.N.M.A.); (M.A.S.); (T.A.)
| | - Ikuo Shoji
- Division of Infectious Disease Control, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; (L.D.); (D.N.M.A.); (M.A.S.); (T.A.)
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13
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Kumar A, Narang RK, Bhatia R. Recent advancements in NS5B inhibitors (2011-2021): Structural insights, SAR studies and clinical status. J Mol Struct 2023; 1293:136272. [DOI: 10.1016/j.molstruc.2023.136272] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/30/2025]
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14
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Elyamany A, Ghazala R, Fayed O, Hamed Y, El-Shendidi A. Mitochondrial DNA copy number in Hepatitis C virus-related chronic liver disease: impact of direct-acting antiviral therapy. Sci Rep 2023; 13:18330. [PMID: 37884543 PMCID: PMC10603142 DOI: 10.1038/s41598-023-44665-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Accepted: 10/11/2023] [Indexed: 10/28/2023] Open
Abstract
Hepatitis C virus (HCV) infection can regulate the number and dynamics of mitochondria, and is associated with a prominent hepatic mitochondrial injury. Mitochondrial distress conveys oxidative damage which is implicated in liver disease progression. The present study was conducted to assess the change of mitochondrial DNA (mtDNA) copy number in patients with HCV-related chronic liver disease and the impact of direct-acting antiviral (DAA) therapy. Whole blood mtDNA copy number was measured using real-time quantitative polymerase chain reaction at baseline and 12 weeks after the end of therapy in 50 treatment-naïve HCV-infected patients who achieved sustained viral response (SVR) after DAA therapy and 20 healthy controls. Whole blood mtDNA copy number appeared significantly lower in HCV-infected patients before therapy compared to healthy subjects (P < 0.001). Post-treatment, there was significant increase of mtDNA copy number in HCV-infected patients at SVR12 compared to the pre-treatment values (P < 0.001), meanwhile it didn't differ significantly between HCV-infected patients after therapy and healthy subjects (P = 0.059). Whole blood mtDNA copy number correlated inversely to the serum bilirubin in HCV-infected patients (P = 0.013), however it didn't correlate significantly to the serum aminotransferases, viral load or fibrosis-4 score (P > 0.05). In conclusion, chronic HCV infection has been associated with a prominent mitochondrial injury which could mediate a progressive liver disease. The improved mtDNA content after DAA therapy highlights a possible potential of these drugs to alleviate mitochondrial damage in HCV-related liver disease.
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Affiliation(s)
- Amany Elyamany
- Department of Internal Medicine (Hepatology Unit), Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Rasha Ghazala
- Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Omnia Fayed
- Department of Clinical and Chemical Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Yasmin Hamed
- Department of Internal Medicine (Hepatology Unit), Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Assem El-Shendidi
- Department of Internal Medicine (Hepatology Unit), Faculty of Medicine, Alexandria University, Alexandria, Egypt.
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15
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Wang C, Chen Y, Hu S, Liu X. Insights into the function of ESCRT and its role in enveloped virus infection. Front Microbiol 2023; 14:1261651. [PMID: 37869652 PMCID: PMC10587442 DOI: 10.3389/fmicb.2023.1261651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 09/20/2023] [Indexed: 10/24/2023] Open
Abstract
The endosomal sorting complex required for transport (ESCRT) is an essential molecular machinery in eukaryotic cells that facilitates the invagination of endosomal membranes, leading to the formation of multivesicular bodies (MVBs). It participates in various cellular processes, including lipid bilayer remodeling, cytoplasmic separation, autophagy, membrane fission and re-modeling, plasma membrane repair, as well as the invasion, budding, and release of certain enveloped viruses. The ESCRT complex consists of five complexes, ESCRT-0 to ESCRT-III and VPS4, along with several accessory proteins. ESCRT-0 to ESCRT-II form soluble complexes that shuttle between the cytoplasm and membranes, mainly responsible for recruiting and transporting membrane proteins and viral particles, as well as recruiting ESCRT-III for membrane neck scission. ESCRT-III, a soluble monomer, directly participates in vesicle scission and release, while VPS4 hydrolyzes ATP to provide energy for ESCRT-III complex disassembly, enabling recycling. Studies have confirmed the hijacking of ESCRT complexes by enveloped viruses to facilitate their entry, replication, and budding. Recent research has focused on the interaction between various components of the ESCRT complex and different viruses. In this review, we discuss how different viruses hijack specific ESCRT regulatory proteins to impact the viral life cycle, aiming to explore commonalities in the interaction between viruses and the ESCRT system.
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Affiliation(s)
- Chunxuan Wang
- Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou, China
| | - Yu Chen
- Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou, China
| | - Shunlin Hu
- Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou, China
| | - Xiufan Liu
- Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou, China
- Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, China
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16
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Toth EA, Andrianov AK, Fuerst TR. Prospects for developing an Hepatitis C virus E1E2-based nanoparticle vaccine. Rev Med Virol 2023; 33:e2474. [PMID: 37565536 PMCID: PMC10626635 DOI: 10.1002/rmv.2474] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 07/31/2023] [Accepted: 08/02/2023] [Indexed: 08/12/2023]
Abstract
Globally, more than 58 million people are chronically infected with Hepatitis C virus (HCV) with 1.5 million new infections occurring each year. An effective vaccine for HCV is therefore a major unmet medical and public health need. Since HCV rapidly accumulates mutations, vaccines must elicit the production of broadly neutralising antibodies (bnAbs) in a reproducible fashion. Decades of research have generated a number of HCV vaccine candidates. Based on the available data and research through clinical development, a vaccine antigen based on the E1E2 glycoprotein complex appears to be the best choice, but robust induction of humoral and cellular responses leading to virus neutralisation has not yet been achieved. One issue that has arisen in developing an HCV vaccine (and many other vaccines as well) is the platform used for antigen delivery. The majority of viral vaccine trials have employed subunit vaccines. However, subunit vaccines often have limited immunogenicity, as seen for HCV, and thus multiple formats must be examined in order to elicit a robust anti-HCV immune response. Nanoparticle vaccines are gaining prominence in the field due to their ability to facilitate a controlled multivalent presentation and trafficking to lymph nodes, where they can interact with both arms of the immune system. This review discusses the potential for development of a nanoparticle-based HCV E1E2 vaccine, with an emphasis on the potential benefits of such an approach along with the major challenges facing the incorporation of E1E2 into nanoparticulate delivery systems and how those challenges can be addressed.
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Affiliation(s)
- Eric A. Toth
- University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD 20850, USA
| | - Alexander K. Andrianov
- University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD 20850, USA
| | - Thomas R. Fuerst
- University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD 20850, USA
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA
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17
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ARIFFIANTO ADI, DENG LIN, HARADA SAKI, LIANG YUJIAO, MATSUI CHIEKO, ABE TAKAYUKI, SHOJI IKUO. Transcription Factor JunB Suppresses Hepatitis C Virus Replication. THE KOBE JOURNAL OF MEDICAL SCIENCES 2023; 69:E86-E95. [PMID: 37661632 PMCID: PMC10695097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 06/28/2023] [Indexed: 09/05/2023]
Abstract
We previously reported that hepatitis C virus (HCV) infection activates the reactive oxygen species (ROS)/c-Jun N-terminal kinase (JNK) signaling pathway. Activation of JNK contributes to the development of liver diseases, including metabolic disorders, steatosis, liver cirrhosis and hepatocellular carcinoma. JNK is known to have numerous target genes, including JunB, a member of activator protein-1 transcription factor family. However, the roles of JunB in the HCV life cycle and HCV-associated pathogenesis remain unclear. To clarify a physiological role of JunB in HCV infection, we investigated the phosphorylation of JunB in HCV J6/JFH1-infected Huh-7.5 cells. Immunoblot analysis revealed that HCV-induced ROS/JNK activation promoted phosphorylation of JunB. The small interfering RNA (siRNA) knockdown of JunB significantly increased the amount of intracellular HCV RNA as well as the intracellular and extracellular HCV infectivity titers. Conversely, overexpression of JunB significantly reduced the amount of intracellular HCV RNA and the intracellular and extracellular HCV infectivity titers. These results suggest that JunB plays a role in inhibiting HCV propagation. Additionally, HCV-mediated JunB activation promoted hepcidin promoter activity and hepcidin mRNA levels, a key factor in modulating iron homeostasis, suggesting that JunB is involved in HCV-induced transcriptional upregulation of hepcidin. Taken together, we propose that the HCV-induced ROS/JNK/JunB signaling pathway plays roles in inhibiting HCV replication and contributing to HCV-mediated iron metabolism disorder.
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Affiliation(s)
- ADI ARIFFIANTO
- Division of Infectious Disease Control, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Japan
| | - LIN DENG
- Division of Infectious Disease Control, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Japan
| | - SAKI HARADA
- Division of Infectious Disease Control, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Japan
| | - YUJIAO LIANG
- Division of Infectious Disease Control, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Japan
| | - CHIEKO MATSUI
- Division of Infectious Disease Control, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Japan
| | - TAKAYUKI ABE
- Division of Infectious Disease Control, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Japan
| | - IKUO SHOJI
- Division of Infectious Disease Control, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Japan
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18
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Chowdhary S, Deka R, Panda K, Kumar R, Solomon AD, Das J, Kanoujiya S, Gupta AK, Sinha S, Ruokolainen J, Kesari KK, Gupta PK. Recent Updates on Viral Oncogenesis: Available Preventive and Therapeutic Entities. Mol Pharm 2023; 20:3698-3740. [PMID: 37486263 PMCID: PMC10410670 DOI: 10.1021/acs.molpharmaceut.2c01080] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 06/13/2023] [Accepted: 06/14/2023] [Indexed: 07/25/2023]
Abstract
Human viral oncogenesis is a complex phenomenon and a major contributor to the global cancer burden. Several recent findings revealed cellular and molecular pathways that promote the development and initiation of malignancy when viruses cause an infection. Even, antiviral treatment has become an approach to eliminate the viral infections and prevent the activation of oncogenesis. Therefore, for a better understanding, the molecular pathogenesis of various oncogenic viruses like, hepatitis virus, human immunodeficiency viral (HIV), human papillomavirus (HPV), herpes simplex virus (HSV), and Epstein-Barr virus (EBV), could be explored, especially, to expand many potent antivirals that may escalate the apoptosis of infected malignant cells while sparing normal and healthy ones. Moreover, contemporary therapies, such as engineered antibodies antiviral agents targeting signaling pathways and cell biomarkers, could inhibit viral oncogenesis. This review elaborates the recent advancements in both natural and synthetic antivirals to control viral oncogenesis. The study also highlights the challenges and future perspectives of using antivirals in viral oncogenesis.
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Affiliation(s)
- Shivam Chowdhary
- Department
of Industrial Microbiology, Sam Higginbottom
University of Agriculture, Technology and Sciences, Prayagraj 211007, Uttar Pradesh India
| | - Rahul Deka
- Department
of Bioengineering and Biotechnology, Birla
Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India
| | - Kingshuk Panda
- Department
of Applied Microbiology, Vellore Institute
of Technology, Vellore 632014, Tamil Nadu, India
| | - Rohit Kumar
- Department
of Life Sciences, Sharda School of Basic Sciences and Research, Sharda University, Greater Noida 201310, Uttar Pradesh, India
| | - Abhishikt David Solomon
- Department
of Molecular & Cellular Engineering, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj 211007, Uttar Pradesh, India
| | - Jimli Das
- Centre
for
Biotechnology and Bioinformatics, Dibrugarh
University, Assam 786004, India
| | - Supriya Kanoujiya
- School
of
Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India
| | - Ashish Kumar Gupta
- Department
of Biophysics, All India Institute of Medical
Sciences, New Delhi 110029, India
| | - Somya Sinha
- Department
of Biotechnology, Graphic Era Deemed to
Be University, Dehradun 248002, Uttarakhand, India
| | - Janne Ruokolainen
- Department
of Applied Physics, School of Science, Aalto
University, 02150 Espoo, Finland
| | - Kavindra Kumar Kesari
- Department
of Applied Physics, School of Science, Aalto
University, 02150 Espoo, Finland
- Division
of Research and Development, Lovely Professional
University, Phagwara 144411, Punjab, India
| | - Piyush Kumar Gupta
- Department
of Life Sciences, Sharda School of Basic Sciences and Research, Sharda University, Greater Noida 201310, Uttar Pradesh, India
- Department
of Biotechnology, Graphic Era Deemed to
Be University, Dehradun 248002, Uttarakhand, India
- Faculty
of Health and Life Sciences, INTI International
University, Nilai 71800, Malaysia
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19
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Gong Z, Yan Z, Liu W, Luo B. Oncogenic viruses and host lipid metabolism: a new perspective. J Gen Virol 2023; 104. [PMID: 37279154 DOI: 10.1099/jgv.0.001861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023] Open
Abstract
As noncellular organisms, viruses do not have their own metabolism and rely on the metabolism of host cells to provide energy and metabolic substances for their life cycles. Increasing evidence suggests that host cells infected with oncogenic viruses have dramatically altered metabolic requirements and that oncogenic viruses produce substances used for viral replication and virion production by altering host cell metabolism. We focused on the processes by which oncogenic viruses manipulate host lipid metabolism and the lipid metabolism disorders that occur in oncogenic virus-associated diseases. A deeper understanding of viral infections that cause changes in host lipid metabolism could help with the development of new antiviral agents as well as potential new therapeutic targets.
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Affiliation(s)
- Zhiyuan Gong
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, PR China
| | - Zhiyong Yan
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, PR China
| | - Wen Liu
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, PR China
| | - Bing Luo
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, PR China
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20
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Mahmoud Farhan S, Mahmoud Abd El-Baky R, Mohammad Abdalla SA, Osama El-Gendy A, Farag Azmy A, Department of Microbiology and Immunology, Faculty of Pharmacy, Deraya University, Minia, Egypt, Department of Microbiology and Immunology, Faculty of Pharmacy, Deraya University, Minia, Egypt, Department of Microbiology and Immunology, Faculty of Pharmacy, Suez Canal University, Ismalia, Egypt, Department of Microbiology and Immunology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt, Department of Microbiology and Immunology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt. Efficacy of Amikacin and Imipenem Against Multi-Drug Resistant Gram-Negative Bacteria Isolated from Wound Infections, Egypt. IRANIAN JOURNAL OF MEDICAL MICROBIOLOGY 2023; 17:218-229. [DOI: 10.30699/ijmm.17.2.218] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
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21
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Hepatitis C Virus-Lipid Interplay: Pathogenesis and Clinical Impact. Biomedicines 2023; 11:biomedicines11020271. [PMID: 36830808 PMCID: PMC9953247 DOI: 10.3390/biomedicines11020271] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/13/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
Hepatitis C virus (HCV) infection represents the major cause of chronic liver disease, leading to a wide range of hepatic diseases, including cirrhosis and hepatocellular carcinoma. It is the leading indication for liver transplantation worldwide. In addition, there is a growing body of evidence concerning the role of HCV in extrahepatic manifestations, including immune-related disorders and metabolic abnormalities, such as insulin resistance and steatosis. HCV depends on its host cells to propagate successfully, and every aspect of the HCV life cycle is closely related to human lipid metabolism. The virus circulates as a lipid-rich particle, entering the hepatocyte via lipoprotein cell receptors. It has also been shown to upregulate lipid biosynthesis and impair lipid degradation, resulting in significant intracellular lipid accumulation (steatosis) and circulating hypocholesterolemia. Patients with chronic HCV are at increased risk for hepatic steatosis, dyslipidemia, and cardiovascular disease, including accelerated atherosclerosis. This review aims to describe different aspects of the HCV viral life cycle as it impacts host lipoproteins and lipid metabolism. It then discusses the mechanisms of HCV-related hepatic steatosis, hypocholesterolemia, and accelerated atherosclerosis.
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22
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Shen C, Jiang X, Li M, Luo Y. Hepatitis Virus and Hepatocellular Carcinoma: Recent Advances. Cancers (Basel) 2023; 15:533. [PMID: 36672482 PMCID: PMC9856776 DOI: 10.3390/cancers15020533] [Citation(s) in RCA: 67] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 01/08/2023] [Accepted: 01/13/2023] [Indexed: 01/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) remains a global health challenge, causing 600,000 deaths each year. Infectious factors, including hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis D virus (HDV), have long been considered the major risk factors for the development and progression of HCC. These pathogens induce hepatocyte transformation through a variety of mechanisms, including insertional mutations caused by viral gene integration, epigenetic changes, and the induction of long-term immune dysfunction. The discovery of these mechanisms, while advancing our understanding of the disease, also provides targets for new diagnostic and therapeutic approaches. In addition, the discovery and research of chronic HEV infection over the past decade indicate that this common hepatitis virus also seems to have the potential to induce HCC. In this review, we provide an overview of recent studies on the link between hepatitis virus and HCC, as well as new diagnostic and therapeutic approaches to HCC based on these findings. Finally, we also discuss the potential relationship between HEV and HCC. In conclusion, these associations will further optimize the diagnosis and treatment of infection-associated HCC and call for better management policies.
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Affiliation(s)
| | | | - Mei Li
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yao Luo
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
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23
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A single mutation in the E2 glycoprotein of hepatitis C virus broadens the claudin specificity for its infection. Sci Rep 2022; 12:20243. [PMID: 36424447 PMCID: PMC9691748 DOI: 10.1038/s41598-022-23824-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 11/07/2022] [Indexed: 11/27/2022] Open
Abstract
Entry of the hepatitis C virus (HCV) into host cells is a multistep process mediated by several host factors, including a tight junction protein claudin-1 (CLDN1). We repeatedly passaged HCV-JFH1-tau, an HCV substrain with higher infectivity, on Huh7.5.1-8 cells. A multi-passaged HCV-JFH1-tau lot was infectious to CLDN1-defective S7-A cells, non-permissive to original HCV-JFH1-tau infection. We identified a single mutation, M706L, in the E2 glycoprotein of the HCV-JFH1-tau lot as an essential mutation for infectivity to S7-A cells. The pseudovirus JFH1/M706L mutant could not infect human embryonic kidney 293 T (HEK293T) cells lacking CLDN family but infected HEK293T cells expressing CLDN1, CLDN6, or CLDN9. Thus, this mutant virus could utilize CLDN1, and other CLDN6 and CLDN9, making HCV possible to infect cells other than hepatocytes. iPS cells, one of the stem cells, do not express CLDN1 but express CLDN6 and other host factors required for HCV infection. We confirmed that the HCV-JFH1-tau-derived mutant with an M706L mutation infected iPS cells in a CLDN6-dependent manner. These results demonstrated that a missense mutation in E2 could broaden the CLDN member specificity for HCV infection. HCV may change its receptor requirement through a single amino acid mutation and infect non-hepatic cells.
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24
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Hess S, Kendall TJ, Pena M, Yamane K, Soong D, Adams L, Truman R, Rambukkana A. In vivo partial reprogramming by bacteria promotes adult liver organ growth without fibrosis and tumorigenesis. Cell Rep Med 2022; 3:100820. [PMID: 36384103 PMCID: PMC9729881 DOI: 10.1016/j.xcrm.2022.100820] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 05/04/2022] [Accepted: 10/18/2022] [Indexed: 11/17/2022]
Abstract
Ideal therapies for regenerative medicine or healthy aging require healthy organ growth and rejuvenation, but no organ-level approach is currently available. Using Mycobacterium leprae (ML) with natural partial cellular reprogramming capacity and its animal host nine-banded armadillos, we present an evolutionarily refined model of adult liver growth and regeneration. In infected armadillos, ML reprogram the entire liver and significantly increase total liver/body weight ratio by increasing healthy liver lobules, including hepatocyte proliferation and proportionate expansion of vasculature, and biliary systems. ML-infected livers are microarchitecturally and functionally normal without damage, fibrosis, or tumorigenesis. Bacteria-induced reprogramming reactivates liver progenitor/developmental/fetal genes and upregulates growth-, metabolism-, and anti-aging-associated markers with minimal change in senescence and tumorigenic genes, suggesting bacterial hijacking of homeostatic, regeneration pathways to promote de novo organogenesis. This may facilitate the unraveling of endogenous pathways that effectively and safely re-engage liver organ growth, with broad therapeutic implications including organ regeneration and rejuvenation.
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Affiliation(s)
- Samuel Hess
- Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, UK; Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh, UK
| | - Timothy J Kendall
- Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, UK; Centre for Inflammation Research, The University of Edinburgh, Edinburgh, UK; Edinburgh Pathology, The University of Edinburgh, Edinburgh, UK
| | - Maria Pena
- US Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, National Hansen's Disease Program, Baton Rouge, LA, USA
| | - Keitaro Yamane
- Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, UK; Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh, UK
| | - Daniel Soong
- Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, UK; Medical Research Council Centre for Reproductive Health, The University of Edinburgh, Edinburgh, UK
| | - Linda Adams
- US Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, National Hansen's Disease Program, Baton Rouge, LA, USA
| | - Richard Truman
- US Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, National Hansen's Disease Program, Baton Rouge, LA, USA; Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USA
| | - Anura Rambukkana
- Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, UK; Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh, UK; Edinburgh Infectious Diseases, The University of Edinburgh, Edinburgh, UK; Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh, UK.
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25
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Belachew B, Gao J, Byrd AK, Raney KD. Hepatitis C virus nonstructural protein NS3 unfolds viral G-quadruplex RNA structures. J Biol Chem 2022; 298:102486. [PMID: 36108740 PMCID: PMC9582721 DOI: 10.1016/j.jbc.2022.102486] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 08/17/2022] [Accepted: 09/03/2022] [Indexed: 11/29/2022] Open
Abstract
Hepatitis C virus (HCV) is a major cause of liver-related diseases and hepatocellular carcinoma. The helicase domain of one of the nonstructural proteins of HCV, NS3 (nonstructural protein 3), is essential for viral replication; however, its specific biological role is still under investigation. Here, we set out to determine the interaction between a purified recombinant full length NS3 and synthetic guanine-rich substrates that represent the conserved G-quadruplex (G4)-forming sequences in the HCV-positive and HCV-negative strands. We performed fluorescence anisotropy binding, G4 reporter duplex unwinding, and G4RNA trapping assays to determine the binding and G4 unfolding activity of NS3. Our data suggest that NS3 can unfold the conserved G4 structures present within the genome and the negative strand of HCV. Additionally, we found the activity of NS3 on a G4RNA was reduced significantly in the presence of a G4 ligand. The ability of NS3 to unfold HCV G4RNA could imply a novel biological role of the viral helicase in replication.
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Affiliation(s)
- Binyam Belachew
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Jun Gao
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Alicia K Byrd
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Kevin D Raney
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
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26
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Wolfisberg R, Thorselius CE, Salinas E, Elrod E, Trivedi S, Nielsen L, Fahnøe U, Kapoor A, Grakoui A, Rice CM, Bukh J, Holmbeck K, Scheel TKH. Neutralization and receptor use of infectious culture-derived rat hepacivirus as a model for HCV. Hepatology 2022; 76:1506-1519. [PMID: 35445423 PMCID: PMC9585093 DOI: 10.1002/hep.32535] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 04/06/2022] [Accepted: 04/08/2022] [Indexed: 12/31/2022]
Abstract
BACKGROUND AND AIMS Lack of tractable immunocompetent animal models amenable to robust experimental challenge impedes vaccine efforts for HCV. Infection with rodent hepacivirus from Rattus norvegicus (RHV-rn1) in rats shares HCV-defining characteristics, including liver tropism, chronicity, and pathology. RHV in vitro cultivation would facilitate genetic studies on particle production, host factor interactions, and evaluation of antibody neutralization guiding HCV vaccine approaches. APPROACH AND RESULTS We report an infectious reverse genetic cell culture system for RHV-rn1 using highly permissive rat hepatoma cells and adaptive mutations in the E2, NS4B, and NS5A viral proteins. Cell culture-derived RHV-rn1 particles (RHVcc) share hallmark biophysical characteristics of HCV and are infectious in mice and rats. Culture adaptive mutations attenuated RHVcc in immunocompetent rats, and the mutations reverted following prolonged infection, but not in severe combined immunodeficiency (SCID) mice, suggesting that adaptive immune pressure is a primary driver of reversion. Accordingly, sera from RHVcc-infected SCID mice or the early acute phase of immunocompetent mice and rats were infectious in culture. We further established an in vitro RHVcc neutralization assay, and observed neutralizing activity of rat sera specifically from the chronic phase of infection. Finally, we found that scavenger receptor class B type I promoted RHV-rn1 entry in vitro and in vivo. CONCLUSIONS The RHV-rn1 infectious cell culture system enables studies of humoral immune responses against hepacivirus infection. Moreover, recapitulation of the entire RHV-rn1 infectious cycle in cell culture will facilitate reverse genetic studies and the exploration of tropism and virus-host interactions.
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Affiliation(s)
- Raphael Wolfisberg
- Copenhagen Hepatitis C ProgramDepartment of Infectious DiseasesHvidovre HospitalCopenhagenDenmark,Department of Immunology and MicrobiologyUniversity of CopenhagenCopenhagenDenmark
| | - Caroline E. Thorselius
- Copenhagen Hepatitis C ProgramDepartment of Infectious DiseasesHvidovre HospitalCopenhagenDenmark,Department of Immunology and MicrobiologyUniversity of CopenhagenCopenhagenDenmark
| | - Eduardo Salinas
- Emory Vaccine CenterDivision of Microbiology and ImmunologyYerkes Research Primate CenterEmory University School of MedicineAtlantaGeorgiaUSA,Division of Infectious DiseasesDepartment of MedicineEmory University School of MedicineAtlantaGeorgiaUSA
| | - Elizabeth Elrod
- Emory Vaccine CenterDivision of Microbiology and ImmunologyYerkes Research Primate CenterEmory University School of MedicineAtlantaGeorgiaUSA,Division of Infectious DiseasesDepartment of MedicineEmory University School of MedicineAtlantaGeorgiaUSA
| | - Sheetal Trivedi
- Center for Vaccines and ImmunityResearch Institute at Nationwide Children’s HospitalColumbusOhioUSA
| | - Louise Nielsen
- Copenhagen Hepatitis C ProgramDepartment of Infectious DiseasesHvidovre HospitalCopenhagenDenmark,Department of Immunology and MicrobiologyUniversity of CopenhagenCopenhagenDenmark
| | - Ulrik Fahnøe
- Copenhagen Hepatitis C ProgramDepartment of Infectious DiseasesHvidovre HospitalCopenhagenDenmark,Department of Immunology and MicrobiologyUniversity of CopenhagenCopenhagenDenmark
| | - Amit Kapoor
- Center for Vaccines and ImmunityResearch Institute at Nationwide Children’s HospitalColumbusOhioUSA
| | - Arash Grakoui
- Emory Vaccine CenterDivision of Microbiology and ImmunologyYerkes Research Primate CenterEmory University School of MedicineAtlantaGeorgiaUSA,Division of Infectious DiseasesDepartment of MedicineEmory University School of MedicineAtlantaGeorgiaUSA
| | - Charles M. Rice
- Laboratory of Virology and Infectious DiseaseThe Rockefeller UniversityNew YorkNew YorkUSA
| | - Jens Bukh
- Copenhagen Hepatitis C ProgramDepartment of Infectious DiseasesHvidovre HospitalCopenhagenDenmark,Department of Immunology and MicrobiologyUniversity of CopenhagenCopenhagenDenmark
| | - Kenn Holmbeck
- Copenhagen Hepatitis C ProgramDepartment of Infectious DiseasesHvidovre HospitalCopenhagenDenmark,Department of Immunology and MicrobiologyUniversity of CopenhagenCopenhagenDenmark
| | - Troels K. H. Scheel
- Copenhagen Hepatitis C ProgramDepartment of Infectious DiseasesHvidovre HospitalCopenhagenDenmark,Department of Immunology and MicrobiologyUniversity of CopenhagenCopenhagenDenmark,Laboratory of Virology and Infectious DiseaseThe Rockefeller UniversityNew YorkNew YorkUSA
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27
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Peng S, Wang H, Wang Z, Wang Q. Progression of Antiviral Agents Targeting Viral Polymerases. Molecules 2022; 27:7370. [PMID: 36364196 PMCID: PMC9654062 DOI: 10.3390/molecules27217370] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/19/2022] [Accepted: 10/20/2022] [Indexed: 08/08/2023] Open
Abstract
Viral DNA and RNA polymerases are two kinds of very important enzymes that synthesize the genetic materials of the virus itself, and they have become extremely favorable targets for the development of antiviral drugs because of their relatively conserved characteristics. There are many similarities in the structure and function of different viral polymerases, so inhibitors designed for a certain viral polymerase have acted as effective universal inhibitors on other types of viruses. The present review describes the development of classical antiviral drugs targeting polymerases, summarizes a variety of viral polymerase inhibitors from the perspective of chemically synthesized drugs and natural product drugs, describes novel approaches, and proposes promising development strategies for antiviral drugs.
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Affiliation(s)
| | | | - Zhengtao Wang
- Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Qingzhong Wang
- Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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28
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Zanelatto ADCO, Lacerda GDS, Accardo CDM, do Rosário NF, da Silva AA, Motta G, Tersariol ILDS, Xavier AR. Cathepsin B and Plasma Kallikrein Are Reliable Biomarkers to Discriminate Clinically Significant Hepatic Fibrosis in Patients with Chronic Hepatitis-C Infection. Microorganisms 2022; 10:1769. [PMID: 36144371 PMCID: PMC9501310 DOI: 10.3390/microorganisms10091769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 11/16/2022] Open
Abstract
We aimed to determine the biomarker performance of the proteolytic enzymes cathepsin B (Cat B) and plasma kallikrein (PKa) and transforming growth factor (TGF)-β to detect hepatic fibrosis (HF) in chronic hepatitis C (CHC) patients. We studied 53 CHC patients and 71 healthy controls (HCs). Hepatic-disease stage was determined by liver biopsies, aminotransferase:platelet ratio index (APRI) and Fibrosis (FIB)4. Hepatic inflammation and HF in CHC patients were stratified using the METAVIR scoring system. Cat-B and PKa activities were monitored fluorometrically. Serum levels of TGF-β (total and its active form) were determined using ELISA-like fluorometric methods. Increased serum levels of Cat B and PKa were found (p < 0.0001) in CHC patients with clinically significant HF and hepatic inflammation compared with HCs. Levels of total TGF-β (p < 0.0001) and active TGF-β (p < 0.001) were increased in CHC patients compared with HCs. Cat-B levels correlated strongly with PKa levels (r = 0.903, p < 0.0001) in CHC patients but did not correlate in HCs. Levels of Cat B, PKa and active TGF-β increased with the METAVIR stage of HF. Based on analyses of receiver operating characteristic (ROC) curves, Cat B and PKa showed high diagnostic accuracy (area under ROC = 0.99 ± 0.02 and 0.991 ± 0.007, respectively) for distinguishing HF in CHC patients from HCs. Taken together, Cat B and PKa could be used as circulating biomarkers to detect HF in HCV-infected patients.
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Affiliation(s)
| | - Gilmar de Souza Lacerda
- Laboratório Multiusuário de Apoio à Pesquisa em Nefrologia e Ciências Médicas, Departamento de Medicina Clínica—LAMAP, Faculdade de Medicina, Universidade Federal Fluminense, Niterói 24033-900, RJ, Brazil
- Departamento de Patologia, Faculdade de Medicina, Universidade Federal Fluminense, Niterói 24033-900, RJ, Brazil
| | - Camila de Melo Accardo
- Departamento de Bioquímica, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04044-020, SP, Brazil
| | - Natalia Fonseca do Rosário
- Laboratório Multiusuário de Apoio à Pesquisa em Nefrologia e Ciências Médicas, Departamento de Medicina Clínica—LAMAP, Faculdade de Medicina, Universidade Federal Fluminense, Niterói 24033-900, RJ, Brazil
| | - Andréa Alice da Silva
- Laboratório Multiusuário de Apoio à Pesquisa em Nefrologia e Ciências Médicas, Departamento de Medicina Clínica—LAMAP, Faculdade de Medicina, Universidade Federal Fluminense, Niterói 24033-900, RJ, Brazil
| | - Guacyara Motta
- Departamento de Bioquímica, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04044-020, SP, Brazil
| | | | - Analucia Rampazzo Xavier
- Laboratório Multiusuário de Apoio à Pesquisa em Nefrologia e Ciências Médicas, Departamento de Medicina Clínica—LAMAP, Faculdade de Medicina, Universidade Federal Fluminense, Niterói 24033-900, RJ, Brazil
- Departamento de Patologia, Faculdade de Medicina, Universidade Federal Fluminense, Niterói 24033-900, RJ, Brazil
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29
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Molecular Epidemiology and Baseline Resistance of Hepatitis C Virus to Direct Acting Antivirals in Croatia. Pathogens 2022; 11:pathogens11070808. [PMID: 35890052 PMCID: PMC9323280 DOI: 10.3390/pathogens11070808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 07/15/2022] [Accepted: 07/18/2022] [Indexed: 02/04/2023] Open
Abstract
Molecular epidemiology of hepatitis C virus (HCV) is exceptionally complex due to the highly diverse HCV genome. Genetic diversity, transmission dynamics, and epidemic history of the most common HCV genotypes were inferred by population sequencing of the HCV NS3, NS5A, and NS5B region followed by phylogenetic and phylodynamic analysis. The results of this research suggest high overall prevalence of baseline NS3 resistance associate substitutions (RAS) (33.0%), moderate prevalence of NS5A RAS (13.7%), and low prevalence of nucleoside inhibitor NS5B RAS (8.3%). Prevalence of RAS significantly differed according to HCV genotype, with the highest prevalence of baseline resistance to NS3 inhibitors and NS5A inhibitors observed in HCV subtype 1a (68.8%) and subtype 1b (21.3%), respectively. Phylogenetic tree reconstructions showed two distinct clades within the subtype 1a, clade I (62.4%) and clade II (37.6%). NS3 RAS were preferentially associated with clade I. Phylogenetic analysis demonstrated that 27 (9.0%) HCV sequences had a presumed epidemiological link with another sequence and classified into 13 transmission pairs or clusters which were predominantly comprised of subtype 3a viruses and commonly detected among intravenous drug users (IDU). Phylodynamic analyses highlighted an exponential increase in subtype 1a and 3a effective population size in the late 20th century, which is a period associated with an explosive increase in the number of IDU in Croatia.
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30
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Tsai WL, Cheng JS, Liu PF, Chang TH, Sun WC, Chen WC, Shu CW. Sofosbuvir induces gene expression for promoting cell proliferation and migration of hepatocellular carcinoma cells. Aging (Albany NY) 2022; 14:5710-5726. [PMID: 35833210 PMCID: PMC9365546 DOI: 10.18632/aging.204170] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 05/13/2022] [Indexed: 11/29/2022]
Abstract
Direct-acting antivirals (DAAs) have achieved a sustained virological response (SVR) rate of 95–99% in treating HCV. Several studies suggested that treatment with sofosbuvir (SOF), one type of DAAs, may be associated with increased risk of developing HCC. The aim of this study is to investigate the potential mechanisms of SOF on the development of HCC. OR-6 (harboring full-length genotype 1b HCV) and Huh 7.5.1 cells were used to examine the effects of SOF on cell proliferation and migration of HCC cells. SOF-upregulated genes in OR-6 cells were inspected using next generation sequencing (NGS)and the clinical significance of these candidate genes was analyzed using The Cancer Genome Atlas (TCGA) database. We found that SOF increased cell proliferation and cell migration in OR-6 and Huh 7.5.1 cells. Several SOF-upregulated genes screened from NGS were confirmed by real-time PCR in OR-6 cells. Among these genes, PHOSPHO2, KLHL23, TRIM39, TSNAX-DISC1 and RPP21 expression were significantly elevated in the tumor tissues compared with the non-tumor tissues of HCC according to TCGA database. High expression of PHOSPHO2 and RPP21 was associated with poor overall survival of HCC patients. Moreover, knockdown of PHOSPHO2-KLHL23, TSNAX-DISC1, TRIM39 and RPP21 diminished cell proliferation and migration increased by SOF in OR-6 and Huh 7.5.1 cells. In conclusion, SOF-upregulated genes promoted HCC cell proliferation and migration, which might be associated with the development of HCC.
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Affiliation(s)
- Wei-Lun Tsai
- Division of General Internal Medicine, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.,School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,School of Nursing, Fooyin University, Kaohsiung, Taiwan
| | - Jin-Shiung Cheng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Pei-Feng Liu
- Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Tsung-Hsien Chang
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan
| | - Wei-Chih Sun
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Wen-Chi Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Chih-Wen Shu
- Institute of BioPharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
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31
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Salama II, Raslan HM, Abdel-Latif GA, Salama SI, Sami SM, Shaaban FA, Abdelmohsen AM, Fouad WA. Impact of direct-acting antiviral regimens on hepatic and extrahepatic manifestations of hepatitis C virus infection. World J Hepatol 2022; 14:1053-1073. [PMID: 35978668 PMCID: PMC9258264 DOI: 10.4254/wjh.v14.i6.1053] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 04/01/2022] [Accepted: 05/22/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is a common cause of liver disease and is associated with various extrahepatic manifestations (EHMs). This mini-review outlines the currently available treatments for HCV infection and their prognostic effect on hepatic manifestations and EHMs. Direct-acting antiviral (DAA) regimens are considered pan-genotypic as they achieve a sustained virological response (SVR) > 85% after 12 wk through all the major HCV genotypes, with high percentages of SVR even in advanced fibrosis and cirrhosis. The risk factors for DAA failure include old males, cirrhosis, and the presence of resistance-associated substitutions (RAS) in the region targeted by the received DAAs. The effectiveness of DAA regimens is reduced in HCV genotype 3 with baseline RAS like A30K, Y93H, and P53del. Moreover, the European Association for the Study of the Liver recommended the identification of baseline RAS for HCV genotype 1a. The higher rate of hepatocellular carcinoma (HCC) after DAA therapy may be related to the fact that DAA regimens are offered to patients with advanced liver fibrosis and cirrhosis, where interferon was contraindicated to those patients. The change in the growth of pre-existing subclinical, undetectable HCC upon DAA treatment might be also a cause. Furthermore, after DAA therapy, the T cell-dependent immune response is much weaker upon HCV clearance, and the down-regulation of TNF-α or the elevated neutrophil to lymphocyte ratio might increase the risk of HCC. DAAs can result in reactivation of hepatitis B virus (HBV) in HCV co-infected patients. DAAs are effective in treating HCV-associated mixed cryoglobulinemia, with clinical and immunological responses, and have rapid and high effectiveness in thrombocytopenia. DAAs improve insulin resistance in 90% of patients, increase glomerular filtration rate, and decrease proteinuria, hematuria and articular manifestations. HCV clearance by DAAs allows a significant improvement in atherosclerosis and metabolic and immunological conditions, with a reduction of major cardiovascular events. They also improve physical function, fatigue, cognitive impairment, and quality of life. Early therapeutic approach with DAAs is recommended as it cure many of the EHMs that are still in a reversible stage and can prevent others that can develop due to delayed treatment.
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Affiliation(s)
- Iman Ibrahim Salama
- Department of Community Medicine Research, National Research Center, Giza 12622, Dokki, Egypt.
| | - Hala M Raslan
- Department of Internal Medicine, National Research Center, Giza 12622, Dokki, Egypt
| | - Ghada A Abdel-Latif
- Department of Community Medicine Research, National Research Center, Giza 12622, Dokki, Egypt
| | - Somaia I Salama
- Department of Community Medicine Research, National Research Center, Giza 12622, Dokki, Egypt
| | - Samia M Sami
- Department of Child Health, National Research Center, Giza 12622, Dokki, Egypt
| | - Fatma A Shaaban
- Department of Child Health, National Research Center, Giza 12622, Dokki, Egypt
| | - Aida M Abdelmohsen
- Department of Community Medicine Research, National Research Center, Giza 12622, Dokki, Egypt
| | - Walaa A Fouad
- Department of Community Medicine Research, National Research Center, Giza 12622, Dokki, Egypt
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32
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Sun Y, Gong L, Yin Y, Zhang L, Sun Q, Feng K, Cui Y, Zhang Q, Zhang X, Deng X, You F, Lu D, Lin Z. A Gradient pH-Sensitive Polymer-Based Antiviral Strategy via Viroporin-Induced Membrane Acidification. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2022; 34:e2109580. [PMID: 35229371 DOI: 10.1002/adma.202109580] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 02/19/2022] [Indexed: 06/14/2023]
Abstract
Lipid-membrane-targeting strategies hold great promise to develop broad-spectrum antivirals. However, it remains a big challenge to identify novel membrane-based targets of viruses and virus-infected cells for development of precision targeted approaches. Here, it is discovered that viroporins, viral-encoded ion channels, which have been reported to mediate release of hydrogen ions, trigger membrane acidification of virus-infected cells. Through development of a fine-scale library of gradient pH-sensitive (GPS) polymeric nanoprobes, the cellular membrane pH transitions are measured from pH 6.8-7.1 (uninfection) to pH 6.5-6.8 (virus-infection). In response to the subtle pH alterations, the GPS polymer with sharp response at pH 6.8 (GPS6.8 ) selectively binds to virus-infected cell membranes or the viral envelope, and even completely disrupts the viral envelope. Accordingly, GPS6.8 treatment exerts suppressive effects on a wide variety of viruses including SARS-CoV-2 through triggering viral-envelope lysis rather than affecting immune pathway or viability of host cells. Murine viral-infection models exhibit that supplementation of GPS6.8 decreases viral titers and ameliorates inflammatory damage. Thus, the gradient pH-sensitive nanotechnology offers a promising strategy for accurate detection of biological pH environments and robust interference with viruses.
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Affiliation(s)
- Yizhe Sun
- Institute of Systems Biomedicine, Department of Pathology, Department of Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, P. R. China
| | - Lidong Gong
- Institute of Systems Biomedicine, Department of Pathology, Department of Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, P. R. China
| | - Yue Yin
- Institute of Systems Biomedicine, Department of Pathology, Department of Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, P. R. China
| | - Lei Zhang
- Institute of Systems Biomedicine, Department of Pathology, Department of Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, P. R. China
| | - Qiangming Sun
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 65018, P. R. China
| | - Kai Feng
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 65018, P. R. China
| | - Yimin Cui
- Department of Pharmacy Administration and Clinical Pharmacy, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Qiang Zhang
- Department of Pharmacy Administration and Clinical Pharmacy, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Xuehui Zhang
- National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Peking University School and Hospital of Stomatology, Beijing, 100081, P. R. China
| | - Xuliang Deng
- National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Peking University School and Hospital of Stomatology, Beijing, 100081, P. R. China
| | - Fuping You
- Institute of Systems Biomedicine, Department of Pathology, Department of Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, P. R. China
| | - Dan Lu
- Institute of Systems Biomedicine, Department of Pathology, Department of Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, P. R. China
| | - Zhiqiang Lin
- Institute of Systems Biomedicine, Department of Pathology, Department of Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, P. R. China
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33
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Khan A, Nawaz M, Ullah S, Rehman IU, Khan A, Saleem S, Zaman N, Shinwari ZK, Ali M, Wei DQ. Core amino acid substitutions in HCV-3a isolates from Pakistan and opportunities for multi-epitopic vaccines. J Biomol Struct Dyn 2022; 40:3753-3768. [PMID: 33246391 DOI: 10.1080/07391102.2020.1850353] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatitis C virus (HCV), which infected 71 million worldwide and about 5%-6% are from Pakistan, is an ssRNA virus, responsible for end-stage liver disease. To date, no effective therapy is available to cure this disease. Hence, it is important to study the most prevalent genotypes infecting human population and design novel vaccine or small molecule inhibitors to control the infections associated with HCV. Therefore, in this study clinical samples (n = 35; HCV-3a) from HCV patients were subjected to Sanger sequencing method. The sequencing of the core gene, which is generally considered as conserved, involved in the detection, quantitation and genotyping of HCV was performed. Multiple mutations, that is, R46C, R70Q, L91C, G60E, N/S105A, P108A, N110I, S116V, G90S, A77G and G145R that could be linked with response to antiviral therapies were detected. Phylogenetic analysis suggests emerging viral isolates are circulating in Pakistan. Using ab initio modelling technique, we predicted the 3D structure of core protein and subjected to molecular dynamics simulation to extract the most stable conformation of the structure for further analysis. Immunoinformatic approaches were used to propose a multi-epitopes vaccine against HCV by using core protein. The vaccine constructs consist of nine CTL and three HTL epitopes joined by different linkers were docked against the two reported Toll-like receptors (TLR-3 and TLR-8). Docking of vaccine construct with TLR-3 and TLR-8 shows proper binding and in silico expression of the vaccine resulted in a CAI value of 0.93. These analyses suggest that specific immune responses may be produced by the proposed vaccine.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Ayyaz Khan
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, Pakistan
| | - Mehboob Nawaz
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, Pakistan
| | - Saeed Ullah
- Saidu Group of Teaching Hospital, Swat, Pakistan
| | - Irshad Ur Rehman
- Center of Biotechnology and Microbiology, University of Peshawar, Peshawar, Pakistan
| | - Abbas Khan
- Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiaotong University, Shanghai, China
| | - Shoaib Saleem
- National Center for Bioinformatics, Quaid-i-Azam University Islamabad, Islamabad, Pakistan
| | - Nasib Zaman
- Center of Biotechnology and Microbiology, University of Swat, Swat, Pakistan
| | - Zabta Khan Shinwari
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, Pakistan.,Pakistan Academy of Sciences, Islamabad, Pakistan
| | - Muhammad Ali
- Department of Biotechnology, Quaid-i-Azam University Islamabad, Islamabad, Pakistan
| | - Dong-Qing Wei
- Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiaotong University, Shanghai, China.,State Key Laboratory of Microbial Metabolism, Shanghai-Islamabad-Belgrade Joint Innovation Center on Antibacterial Resistances, Joint Laboratory of International Cooperation in Metabolic and Developmental Sciences, Ministry of Education and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, P.R. China.,Peng Cheng Laboratory, Shenzhen, Guangdong, P.R China
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34
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Sequential Phosphorylation of Hepatitis C Virus NS5A Protein Requires the ATP-Binding Domain of NS3 Helicase. J Virol 2022; 96:e0010722. [PMID: 35293767 DOI: 10.1128/jvi.00107-22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The propagation of the hepatitis C virus (HCV) is regulated in part by the phosphorylation of its nonstructural protein NS5A that undergoes sequential phosphorylation on several highly conserved serine residues and switches from a hypo- to a hyperphosphorylated state. Previous studies have shown that NS5A sequential phosphorylation requires NS3 encoded on the same NS3-NS4A-NS4B-NS5A polyprotein. Subtle mutations in NS3 without affecting its protease activity could affect NS5A phosphorylation. Given the ATPase domain in the NS3 COOH terminus, we tested whether NS3 participates in NS5A phosphorylation similarly to the nucleoside diphosphate kinase-like activity of the rotavirus NSP2 nucleoside triphosphatase (NTPase). Mutations in the NS3 ATP-binding motifs blunted NS5A hyperphosphorylation and phosphorylation at serines 225, 232, and 235, whereas a mutation in the RNA-binding domain did not. The phosphorylation events were not rescued with wild-type NS3 provided in trans. When provided with an NS3 ATPase-compatible ATP analog, N6-benzyl-ATP-γ-S, thiophosphorylated NS5A was detected in the cells expressing the wild-type NS3-NS5B polyprotein. The thiophosphorylation level was lower in the cells expressing NS3-NS5B with a mutation in the NS3 ATP-binding domain. In vitro assays with a synthetic peptide and purified wild-type NS3 followed by dot blotting and mass spectrometry found weak NS5A phosphorylation at serines 222 and 225 that was sensitive to an inhibitor of casein kinase Iα but not helicase. When casein kinase Iα was included in the assay, much stronger phosphorylation was observed at serines 225, 232, and 235. We concluded that NS5A sequential phosphorylation requires the ATP-binding domain of the NS3 helicase and that casein kinase Iα is a potent NS5A kinase. IMPORTANCE For more than 20 years, NS3 was known to participate in NS5A sequential phosphorylation. In the present study, we show for the first time that the ATP-binding domain of NS3 is involved in NS5A phosphorylation. In vitro assays showed that casein kinase Iα is a very potent kinase responsible for NS5A phosphorylation at serines 225, 232, and 235. Our data suggest that ATP binding by NS3 probably results in conformational changes that recruit casein kinase Iα to phosphorylate NS5A, initially at S225 and subsequently at S232 and S235. Our discovery reveals intricate requirements of the structural integrity of NS3 for NS5A hyperphosphorylation and HCV replication.
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35
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Alhetheel AF. Impact of Hepatitis C Virus Infection of Peripheral Blood Mononuclear Cells on the Immune System. FRONTIERS IN VIROLOGY 2022. [DOI: 10.3389/fviro.2021.810231] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hepatitis C is a worldwide liver disease caused by hepatitis C virus (HCV) infection. The virus causes acute and chronic liver inflammation, and it is transmitted mainly by exposure to contaminated blood. HCV is capable of infecting hepatocytes and peripheral blood mononuclear cells, causing complications and disease progression. This mini review provides an overview of HCV infection, including details on the virological aspects, infection of the immune cells, and its impact on the immune system.
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Hepatitis C virus (HCV)-induced ROS/JNK signaling pathway activates the E3 ubiquitin ligase Itch to promote the release of HCV particles via polyubiquitylation of VPS4A. J Virol 2022; 96:e0181121. [PMID: 35044214 DOI: 10.1128/jvi.01811-21] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
We previously reported that hepatitis C virus (HCV) infection activates the reactive oxygen species (ROS)/c-Jun N-terminal kinase (JNK) signaling pathway. However, the roles of ROS/JNK activation in the HCV life cycle still remain unclear. We sought to identify a novel role of ROS/JNK signaling pathway in the HCV life cycle. Immunoblot analysis revealed that HCV-induced ROS/JNK activation promoted phosphorylation of Itch, a HECT-type E3 ubiquitin ligase, leading to activation of Itch. The siRNA-knockdown of Itch significantly reduced the extracellular HCV infectivity titers, HCV RNA, and HCV core protein without affecting intracellular HCV infectivity titers, HCV RNA, and HCV proteins, suggesting that Itch is involved in release of HCV particles. HCV-mediated JNK/Itch activation specifically promoted polyubiquitylation of an AAA-type ATPase VPS4A, but not VPS4B, required to form multivesicular bodies. Site-directed mutagenesis revealed that two lysine residues (K23 and K121) on VPS4A were important for VPS4A polyubiquitylation. The siRNA-knockdown of VPS4A, but not VPS4B, significantly reduced extracellular HCV infectivity titers. Co-immunoprecipitation analysis revealed that HCV infection specifically enhanced the interaction between CHMP1B, a subunit of endosomal sorting complexes required for transport (ESCRT)-III complex, and VPS4A, but not VPS4B, whereas VPS4A K23R/K121R greatly reduced the interaction with CHMP1B. HCV infection significantly increased ATPase activity of VPS4A, but not VPS4A K23R/K121R or VPS4B, suggesting that HCV-mediated polyubiquitylation of VPS4A contributes to activation of VPS4A. Taken together, we propose that HCV-induced ROS/JNK/Itch signaling pathway promotes VPS4A polyubiquitylation, leading to enhanced VPS4A-CHMP1B interaction and promotion of VPS4A ATPase activity, thereby promoting the release of HCV particles. IMPORTANCE ROS/JNK signaling pathway contributes to liver diseases, including steatosis, metabolic disorders, and hepatocellular carcinoma. We previously reported that HCV activates the ROS/JNK signaling pathway, leading to the enhancement of hepatic gluconeogenesis and apoptosis induction. This study further demonstrates that HCV-induced ROS/JNK signaling pathway activates the E3 ubiquitin ligase Itch to promote release of HCV particles via polyubiquitylation of VPS4A. We provide evidence suggesting that HCV infection promotes the ROS/JNK/Itch signaling pathway and ESCRT/VPS4A machinery to release infectious HCV particles. Our results may lead to a better understanding of the mechanistic details of HCV particle release.
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Sabariegos R, Ortega-Prieto AM, Díaz-Martínez L, Grande-Pérez A, García Crespo C, Gallego I, de Ávila AI, Albentosa-González L, Soria ME, Gastaminza P, Domingo E, Perales C, Mas A. Guanosine inhibits hepatitis C virus replication and increases indel frequencies, associated with altered intracellular nucleotide pools. PLoS Pathog 2022; 18:e1010210. [PMID: 35085375 PMCID: PMC8794218 DOI: 10.1371/journal.ppat.1010210] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 12/16/2021] [Indexed: 12/30/2022] Open
Abstract
In the course of experiments aimed at deciphering the inhibition mechanism of mycophenolic acid and ribavirin in hepatitis C virus (HCV) infection, we observed an inhibitory effect of the nucleoside guanosine (Gua). Here, we report that Gua, and not the other standard nucleosides, inhibits HCV replication in human hepatoma cells. Gua did not directly inhibit the in vitro polymerase activity of NS5B, but it modified the intracellular levels of nucleoside di- and tri-phosphates (NDPs and NTPs), leading to deficient HCV RNA replication and reduction of infectious progeny virus production. Changes in the concentrations of NTPs or NDPs modified NS5B RNA polymerase activity in vitro, in particular de novo RNA synthesis and template switching. Furthermore, the Gua-mediated changes were associated with a significant increase in the number of indels in viral RNA, which may account for the reduction of the specific infectivity of the viral progeny, suggesting the presence of defective genomes. Thus, a proper NTP:NDP balance appears to be critical to ensure HCV polymerase fidelity and minimal production of defective genomes.
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Affiliation(s)
- Rosario Sabariegos
- Laboratorio de Virología Molecular, Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla-La Mancha, Albacete, Spain
- Facultad de Medicina, Universidad de Castilla-La Mancha, Albacete, Spain
- Unidad de Biomedicina UCLM-CSIC, Albacete, Spain
| | - Ana María Ortega-Prieto
- Centro de Biología Molecular “Severo Ochoa”, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Campus de Cantoblanco, Madrid, Spain
| | - Luis Díaz-Martínez
- Instituto de Hortofruticultura Subtropical y Mediterránea "La Mayora," Universidad de Málaga-Consejo Superior de Investigaciones Científicas (IHMS-UMA-CSIC), Málaga, Spain
- Área de Genética, Facultad de Ciencias, Universidad de Málaga, Málaga, Spain
| | - Ana Grande-Pérez
- Instituto de Hortofruticultura Subtropical y Mediterránea "La Mayora," Universidad de Málaga-Consejo Superior de Investigaciones Científicas (IHMS-UMA-CSIC), Málaga, Spain
- Área de Genética, Facultad de Ciencias, Universidad de Málaga, Málaga, Spain
| | - Carlos García Crespo
- Centro de Biología Molecular “Severo Ochoa”, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Campus de Cantoblanco, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, Madrid, Spain
| | - Isabel Gallego
- Centro de Biología Molecular “Severo Ochoa”, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Campus de Cantoblanco, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, Madrid, Spain
| | - Ana I. de Ávila
- Centro de Biología Molecular “Severo Ochoa”, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Campus de Cantoblanco, Madrid, Spain
| | - Laura Albentosa-González
- Laboratorio de Virología Molecular, Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla-La Mancha, Albacete, Spain
| | - María Eugenia Soria
- Centro de Biología Molecular “Severo Ochoa”, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Campus de Cantoblanco, Madrid, Spain
- Department of Clinical Microbiology, IIS-Fundación Jiménez Díaz, UAM, Madrid, Spain
| | - Pablo Gastaminza
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, Madrid, Spain
- Department of Cellular and Molecular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain
| | - Esteban Domingo
- Unidad de Biomedicina UCLM-CSIC, Albacete, Spain
- Centro de Biología Molecular “Severo Ochoa”, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Campus de Cantoblanco, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, Madrid, Spain
- * E-mail: (AM); (CP); (ED)
| | - Celia Perales
- Centro de Biología Molecular “Severo Ochoa”, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Campus de Cantoblanco, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, Madrid, Spain
- Department of Clinical Microbiology, IIS-Fundación Jiménez Díaz, UAM, Madrid, Spain
- * E-mail: (AM); (CP); (ED)
| | - Antonio Mas
- Laboratorio de Virología Molecular, Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla-La Mancha, Albacete, Spain
- Unidad de Biomedicina UCLM-CSIC, Albacete, Spain
- Facultad de Farmacia, Universidad de Castilla-La Mancha, Albacete, Spain
- * E-mail: (AM); (CP); (ED)
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Mori Y, Matsuda S, Sato M, Muraoka M, Suzuki Y, Tatsumi A, Nakayama Y, Inoue T, Maekawa S, Enomoto N. The Impact of Antiviral Therapy for Hepatitis C Virus on the Survival of Patients after Hepatocellular Carcinoma Treatment. Intern Med 2022; 61:2721-2729. [PMID: 36104175 PMCID: PMC9556239 DOI: 10.2169/internalmedicine.8456-21] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Objective Owing to advances in direct-acting antiviral (DAA) therapy, a considerable number of patients with hepatitis C virus (HCV)-positive hepatocellular carcinoma (HCC) are now able to achieve a sustained viral response (SVR) after curative treatment of HCC. However, the beneficial effect of a DAA-SVR on the survival remains unclear. Methods A total of 205 patients with HCC who were HCV-positive with Child-Pugh A at the onset from 2008 to 2018 were categorized into 2 groups: 140 patients untreated for HCV throughout the entire course after HCC development (untreated group) and 65 patients treated for HCV with DAAs following HCC treatment who achieved an SVR (SVR group). After propensity score matching, 63 patients from each group were selected. Using these patients, the survival and maintenance of Child-Pugh A after HCC treatment were compared between the untreated group and SVR group. Results There was a significant difference in the overall survival (p<0.001) and the rate of maintaining Child-Pugh A (p<0.001) between the groups. The 5-year survival rates were 96% (SVR group) and 60% (untreated group), and the proportions of patients with Child-Pugh A at 5 years after HCC treatment were 96% (SVR group) and 38% (untreated group). Conclusion In patients with HCV-positive HCC, achieving a DAA-SVR after HCC treatment significantly improved the overall survival rate compared with HCV-untreated patients. The contribution of DAA-SVR during the course of HCC treatment to a longer survival is mainly due to the prevention of the progression of Child-Pugh A to B/C. Further research is needed to determine whether aggressive antiviral therapy is also effective for HCC patients with Child-Pugh B/C.
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Affiliation(s)
- Yuki Mori
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Japan
| | - Shuya Matsuda
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Japan
| | - Mitsuaki Sato
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Japan
| | - Masaru Muraoka
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Japan
| | - Yuichiro Suzuki
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Japan
| | - Akihisa Tatsumi
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Japan
| | - Yasuhiro Nakayama
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Japan
| | - Taisuke Inoue
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Japan
| | - Shinya Maekawa
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Japan
| | - Nobuyuki Enomoto
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Japan
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Mitra S, Anand U, Sanyal R, Jha NK, Behl T, Mundhra A, Ghosh A, Radha, Kumar M, Proćków J, Dey A. Neoechinulins: Molecular, cellular, and functional attributes as promising therapeutics against cancer and other human diseases. Biomed Pharmacother 2021; 145:112378. [PMID: 34741824 DOI: 10.1016/j.biopha.2021.112378] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 10/23/2021] [Accepted: 10/25/2021] [Indexed: 12/21/2022] Open
Abstract
Neoechinulins are fungal and plant-derived chemicals extracted from Microsporum sp., Eurotium rubrum, Aspergillus sp., etc. Two analogues of neoechinulin, i.e., A and B, exerted extensive pharmacological properties described in this review. Neoechinulin is an indole alkaloid and has a double bond between C8/C9, which tends to contribute to its cytoprotective nature. Neoechinulin A exhibits protection to PC12 cells against nitrosative stress via increasing NAD(P)H reserve capacity and decreasing cellular GSH levels. It also confers protection via rescuing PC12 cells from rotenone-induced stress by lowering LDH leakage. This compound has great positive potential against neurodegenerative diseases by inhibiting SIN-1 induced cell death in neuronal cells. Together with these, neoechinulin A tends to inhibit Aβ42-induced microglial activation and confers protection against neuroinflammation. Alongside, it also inhibits cervical cancer cells by caspase-dependent apoptosis and via upregulation of apoptosis inducing genes like Bax, it suppresses LPS-induced inflammation in RAW264.7 macrophages and acts as an antidepressant. Whereas, another analogue, Neoechinulin B tends to interfere with the cellular mechanism thereby, inhibiting the entry of influenza A virus and it targets Liver X receptor (LXR) and decreases the infection rate of Hepatitis C. The present review describes the pharmaceutical properties of neoechinulins with notes on their molecular, cellular, and functional basis and their therapeutic properties.
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Affiliation(s)
- Sicon Mitra
- Department of Biotechnology, School of Engineering & Technology, Sharda University, Greater Noida 201310, Uttar Pradesh, India
| | - Uttpal Anand
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
| | - Rupa Sanyal
- Department of Botany, Bhairab Ganguly College (affiliated to West Bengal State University), Feeder Road, Belghoria, Kolkata 700056, West Bengal, India
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering & Technology, Sharda University, Greater Noida 201310, Uttar Pradesh, India
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India
| | - Avinash Mundhra
- Department of Botany, Rishi Bankim Chandra College (Affiliated to the West Bengal State University), East Kantalpara, North 24 Parganas, Naihati 743165, West Bengal, India
| | - Arabinda Ghosh
- Department of Botany, Gauhati University, Guwahati, Assam 781014, India
| | - Radha
- School of Biological and Environmental Sciences, Shoolini University of Biotechnology and Management Sciences, Solan, Himachal Pradesh 173229, India
| | - Manoj Kumar
- Chemical and Biochemical Processing Division, ICAR - Central Institute for Research on Cotton Technology, Mumbai 400019, Maharashtra, India
| | - Jarosław Proćków
- Department of Plant Biology, Institute of Environmental Biology, Wrocław University of Environmental and Life Sciences, Kożuchowska 5b, 51-631 Wrocław, Poland.
| | - Abhijit Dey
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, 700073, West Bengal, India.
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Lee H, Jarhad DB, Lee A, Lee C, Jeong LS. 4′‐Selenonucleosides: Regio‐ and Stereoselective Synthesis of Novel Ribavirin and Acadesine Analogs as Anti‐Hepatitis C Virus (HCV) Agents. ASIAN J ORG CHEM 2021. [DOI: 10.1002/ajoc.202100563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
- Hyejin Lee
- Research Institute of Pharmaceutical Sciences College of Pharmacy Seoul National University Seoul 08826 (Republic of Korea
| | - Dnyandev B. Jarhad
- Research Institute of Pharmaceutical Sciences College of Pharmacy Seoul National University Seoul 08826 (Republic of Korea
| | - Ahrim Lee
- College of Pharmacy Dongguk University-Seoul Goyang 10326 (Republic of Korea
| | - Choongho Lee
- College of Pharmacy Dongguk University-Seoul Goyang 10326 (Republic of Korea
| | - Lak Shin Jeong
- Research Institute of Pharmaceutical Sciences College of Pharmacy Seoul National University Seoul 08826 (Republic of Korea
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Sheikh AY, Mattei A, Miglani Bhardwaj R, Hong RS, Abraham NS, Schneider-Rauber G, Engstrom KM, Diwan M, Henry RF, Gao Y, Juarez V, Jordan E, DeGoey DA, Hutchins CW. Implications of the Conformationally Flexible, Macrocyclic Structure of the First-Generation, Direct-Acting Anti-Viral Paritaprevir on Its Solid Form Complexity and Chameleonic Behavior. J Am Chem Soc 2021; 143:17479-17491. [PMID: 34637297 DOI: 10.1021/jacs.1c06837] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Direct-acting antiviral regimens have transformed therapeutic management of hepatitis C across all prevalent genotypes. Most of the chemical matter in these regimens comprises molecules well outside the traditional drug development chemical space and presents significant challenges. Herein, the implications of high conformational flexibility and the presence of a 15-membered macrocyclic ring in paritaprevir are studied through a combination of advanced computational and experimental methods with focus on molecular chameleonicity and crystal form complexity. The ability of the molecule to toggle between high and low 3D polar surface area (PSA) conformations is underpinned by intramolecular hydrogen bonding (IMHB) interactions and intramolecular steric effects. Computational studies consequently show a very significant difference of over 75 Å2 in 3D PSA between polar and apolar environments and provide the structural basis for the perplexingly favorable passive permeability of the molecule. Crystal packing and protein binding resulting in strong intermolecular interactions disrupt these intramolecular interactions. Crystalline Form I benefits from strong intermolecular interactions, whereas the weaker intermolecular interactions in Form II are partially compensated by the energetic advantage of an IMHB. Like Form I, no IMHB is observed within the receptor-bound conformation; instead, an intermolecular H-bond contributes to the potency of the molecule. The choice of metastable Form II is derisked through strategies accounting for crystal surface and packing features to manage higher form specific solid-state chemical reactivity and specific processing requirements. Overall, the results show an unambiguous link between structural features and derived properties from crystallization to dissolution, permeation, and docking into the protein pocket.
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Affiliation(s)
- Ahmad Y Sheikh
- Research & Development, AbbVie Inc., 1 N Waukegan Road, North Chicago, Illinois 60064, United States
| | - Alessandra Mattei
- Research & Development, AbbVie Inc., 1 N Waukegan Road, North Chicago, Illinois 60064, United States
| | - Rajni Miglani Bhardwaj
- Research & Development, AbbVie Inc., 1 N Waukegan Road, North Chicago, Illinois 60064, United States
| | - Richard S Hong
- Research & Development, AbbVie Inc., 1 N Waukegan Road, North Chicago, Illinois 60064, United States
| | - Nathan S Abraham
- Research & Development, AbbVie Inc., 1 N Waukegan Road, North Chicago, Illinois 60064, United States
| | - Gabriela Schneider-Rauber
- Research & Development, AbbVie Inc., 1 N Waukegan Road, North Chicago, Illinois 60064, United States
| | - Kenneth M Engstrom
- Research & Development, AbbVie Inc., 1 N Waukegan Road, North Chicago, Illinois 60064, United States
| | - Moiz Diwan
- Research & Development, AbbVie Inc., 1 N Waukegan Road, North Chicago, Illinois 60064, United States
| | - Rodger F Henry
- Research & Development, AbbVie Inc., 1 N Waukegan Road, North Chicago, Illinois 60064, United States
| | - Yi Gao
- Research & Development, AbbVie Inc., 1 N Waukegan Road, North Chicago, Illinois 60064, United States
| | - Vivian Juarez
- Research & Development, AbbVie Inc., 1 N Waukegan Road, North Chicago, Illinois 60064, United States
| | - Erin Jordan
- Research & Development, AbbVie Inc., 1 N Waukegan Road, North Chicago, Illinois 60064, United States
| | - David A DeGoey
- Research & Development, AbbVie Inc., 1 N Waukegan Road, North Chicago, Illinois 60064, United States
| | - Charles W Hutchins
- Research & Development, AbbVie Inc., 1 N Waukegan Road, North Chicago, Illinois 60064, United States
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Kao C, Surjit M, Ranjith-Kumar CT. Editorial: Viral Hepatitis: Pathophysiology, Prevention, and Control. Front Cell Infect Microbiol 2021; 11:633580. [PMID: 34513722 PMCID: PMC8427190 DOI: 10.3389/fcimb.2021.633580] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 07/09/2021] [Indexed: 11/13/2022] Open
Affiliation(s)
- Cheng Kao
- Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN, United States
| | - Milan Surjit
- Vaccine and Infectious Disease Research Center, Translational Health Science and Technology Institute (THSTI), Faridabad, India
| | - C T Ranjith-Kumar
- University School of Biotechnology, Guru Gobind Singh Indraprastha University, New Delhi, India
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Yamashita Y, Joshita S, Sugiura A, Yamazaki T, Kobayashi H, Wakabayashi SI, Yamada Y, Shibata S, Kunimoto H, Iwadare T, Matsumura M, Miyabayashi C, Okumura T, Ozawa S, Nozawa Y, Kobayashi N, Komatsu M, Fujimori N, Saito H, Umemura T. aMAP score prediction of hepatocellular carcinoma occurrence and incidence-free rate after a sustained virologic response in chronic hepatitis C. Hepatol Res 2021; 51:933-942. [PMID: 34216422 DOI: 10.1111/hepr.13689] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 06/14/2021] [Accepted: 06/25/2021] [Indexed: 02/08/2023]
Abstract
AIMS Hepatocellular carcinoma (HCC) can still occur in hepatitis C virus (HCV) patients who have achieved a sustained virologic response (SVR), which remains an important clinical issue in the direct-acting antivirals era. The current study investigated the clinical utility of the aMAP score (consisting of age, male, albumin-bilirubin, and platelets) for predicting HCC occurrence in HCV patients achieving an SVR by direct-acting antivirals. METHODS A total of 1113 HCV patients without HCC history, all of whom achieved an SVR, were enrolled for clinical comparisons. RESULTS Hepatocellular carcinoma was recorded in 50 patients during a median follow-up period of 3.7 years. The aMAP score was significantly higher in the HCC occurrence group than in the HCC-free group (53 vs. 47, p < 0.001). According to risk stratification based on aMAP score, the cumulative incidence of HCC occurrence for the low-, medium-, and high-risk groups was 0.14%, 4.49%, and 9.89%, respectively, at 1 year and 1.56%, 6.87%, and 16.17%, respectively, at 3 years (low vs. medium, low vs. high, and medium vs. high: all p < 0.01). Cox proportional hazard analysis confirmed aMAP ≥ 50 (hazard ratio [HR]: 2.78, p = 0.014), age≥ 70 years (HR: 2.41, p = 0.028), ALT ≥ 17 U/L (HR: 2.14, p < 0.001), and AFP ≥ 10 ng/mL (HR: 2.89, p = 0.005) as independent risk factors of HCC occurrence. Interestingly, all but one patient (99.5%) with aMAP less than 40 was HCC-free following an SVR. CONCLUSION The aMAP score could have clinical utility for predicting HCC occurrence in HCV patients achieving an SVR.
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Affiliation(s)
- Yuki Yamashita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Satoru Joshita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Ayumi Sugiura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Tomoo Yamazaki
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Hiroyuki Kobayashi
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Shun-Ichi Wakabayashi
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yosuke Yamada
- Department of Nephrology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Soichiro Shibata
- Department of Gastroenterology, Japanese Red Cross Society Nagano Hospital, Nagano, Japan
| | - Hideo Kunimoto
- Department of Gastroenterology, Nagano Municipal Hospital, Nagano, Japan
| | - Takanobu Iwadare
- Department of Gastroenterology, Nagano Municipal Hospital, Nagano, Japan
| | - Makiko Matsumura
- Department of Gastroenterology, Nagano Chuo Hospital, Nagano, Japan
| | | | - Taiki Okumura
- Department of Gastroenterology, NHO Matsumoto Medical Center, Matsumoto, Japan
| | - Sachie Ozawa
- Department of Internal Medicine, Nagano Prefectural Kiso Hospital, Kiso, Japan
| | - Yuichi Nozawa
- Department of Gastroenterology, Ina Central Hospital, Ina, Japan
| | | | - Michiharu Komatsu
- Department of Gastroenterology, Japanese Red Cross Society Suwa Hospital, Suwa, Japan
| | - Naoyuki Fujimori
- Department of Gastroenterology, NHO Shinshu Ueda Medical Center, Ueda, Japan
| | - Hiromi Saito
- Department of Gastroenterology, Aizawa Hospital, Matsumoto, Japan
| | - Takeji Umemura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan.,Department of Life Innovation, Institute for Biomedical Sciences, Shinshu University, Matsumoto, Japan
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Mahnoor, Noreen M, Imran M, Safi SZ, Bashir MA, Alkhuriji AF, Alomar SY, Alharbi HM. Association of blood groups with hepatitis C viremia. Saudi J Biol Sci 2021; 28:5359-5363. [PMID: 34466115 PMCID: PMC8381043 DOI: 10.1016/j.sjbs.2021.05.062] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/10/2021] [Accepted: 05/24/2021] [Indexed: 12/09/2022] Open
Abstract
Hepatitis C virus remained a public health problem with approximately half of the patients untreated and undiagnosed. Chronic HCV is a leading cause of cirrhosis, fibrosis, hepatocellular carcinoma and other hepatic morbidities. Active HCV has a prevalence rate of about 1% (71 million). By July, 2019, 10 million population of Pakistan was declared to have active HCV infection. According to World Health Organization, 23,720 people died of hepatitis-related complexities in Pakistan in 2016. Individuals with certain types of ABO blood groups were more susceptible to diverse kinds of infections. For instance, blood types A and AB predisposed individuals to severe malaria, while type O conferred resistance to the many of the protozoan agent. This study was designed to explore the association of hepatitis C viremia to blood groups, Rh factors, age and gender distribution among Pakistani population. Total 246 participants were screened for HCV in Taqwa diagnostics laboratory, Multan and 200 were found positive. They were divided into 4 groups on the basis of their age. First group included patients ranging from 17 to 25 (52), second, third and fourth group included patients from 26 to 34 (92), 35 to 43 (42) and 44 to above (14) respectively. Confirmed Hepatitis C patients were subjected to analysis of blood group, Rh factor and viral load. Results demonstrated that patients having 'O' blood group (60.37%) were reported for high viral load than any of the other blood groups in the patients of Southern Punjab, Pakistan. Furthermore, Rh-negative factor (26.42) was associated with high viral load than that of the Rh-positive factor (73.58). Disclosure practiced that age group (26-34) was reported for the high viral load than that of the any other group of this study. Females were more aggressively affected by HCV Viremia than male because the mean viral load among the females was higher than that of the males. Greater social awareness and gender-sensitive healthcare is necessary to improve the experiences of patients with HCV.
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Affiliation(s)
- Mahnoor
- Department of Zoology, The Women University Multan, Multan, Pakistan
| | - Mamoona Noreen
- Department of Zoology, The Women University Multan, Multan, Pakistan
| | - Muhammad Imran
- Department of Microbiology, University of Health Sciences, Lahore, Pakistan
| | - Sher Zaman Safi
- Interdisciplinary Research Center in Biomedical Materials (IRCBM), COMSATS Institute of Information Technology, Lahore, Pakistan
| | - Muhammad Amjad Bashir
- Department of Plant Protection faculty of Agricultural Sciences Ghazi University Dera Ghazi Khan Punjab, Pakistan
| | - Afrah Fahad Alkhuriji
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Suliman Yousef Alomar
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Hanan Mualla Alharbi
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
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45
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Gobran ST, Ancuta P, Shoukry NH. A Tale of Two Viruses: Immunological Insights Into HCV/HIV Coinfection. Front Immunol 2021; 12:726419. [PMID: 34456931 PMCID: PMC8387722 DOI: 10.3389/fimmu.2021.726419] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 07/26/2021] [Indexed: 12/13/2022] Open
Abstract
Nearly 2.3 million individuals worldwide are coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Odds of HCV infection are six times higher in people living with HIV (PLWH) compared to their HIV-negative counterparts, with the highest prevalence among people who inject drugs (PWID) and men who have sex with men (MSM). HIV coinfection has a detrimental impact on the natural history of HCV, including higher rates of HCV persistence following acute infection, higher viral loads, and accelerated progression of liver fibrosis and development of end-stage liver disease compared to HCV monoinfection. Similarly, it has been reported that HCV coinfection impacts HIV disease progression in PLWH receiving anti-retroviral therapies (ART) where HCV coinfection negatively affects the homeostasis of CD4+ T cell counts and facilitates HIV replication and viral reservoir persistence. While ART does not cure HIV, direct acting antivirals (DAA) can now achieve HCV cure in nearly 95% of coinfected individuals. However, little is known about how HCV cure and the subsequent resolution of liver inflammation influence systemic immune activation, immune reconstitution and the latent HIV reservoir. In this review, we will summarize the current knowledge regarding the pathogenesis of HIV/HCV coinfection, the effects of HCV coinfection on HIV disease progression in the context of ART, the impact of HIV on HCV-associated liver morbidity, and the consequences of DAA-mediated HCV cure on immune reconstitution and HIV reservoir persistence in coinfected patients.
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Affiliation(s)
- Samaa T Gobran
- Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.,Département de microbiologie, infectiologie et immunologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada.,Department of Medical Microbiology and Immunology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Petronela Ancuta
- Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.,Département de microbiologie, infectiologie et immunologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
| | - Naglaa H Shoukry
- Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.,Département de médecine, Faculté de médecine, Université de Montréal, Montréal, QC, Canada
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46
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Onabajo OO, Wang F, Lee MH, Florez-Vargas O, Obajemu A, Tanikawa C, Vargas JM, Liao SF, Song C, Huang YH, Shen CY, Banday AR, O’Brien TR, Hu Z, Matsuda K, Prokunina-Olsson L. Intracellular Accumulation of IFN-λ4 Induces ER Stress and Results in Anti-Cirrhotic but Pro-HCV Effects. Front Immunol 2021; 12:692263. [PMID: 34497603 PMCID: PMC8419317 DOI: 10.3389/fimmu.2021.692263] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 08/02/2021] [Indexed: 01/09/2023] Open
Abstract
IFNL3/IFNL4 polymorphisms are inversely associated with the risk of chronic hepatitis C virus (HCV) infection and cirrhosis, two major risk factors for developing hepatocellular carcinoma (HCC). To further explore these inverse associations and their molecular underpinnings, we analyzed IFNL3/IFNL4 polymorphisms represented by the IFNL4 genotype (presence of rs368234815-dG or rs12979860-T alleles) in HCV patients: 2969 from Japan and 2931 from Taiwan. IFNL4 genotype was associated with an increased risk of HCV-related HCC (OR=1.28, 95%CI=1.07-1.52, P=0.0058) in the general population of Japanese patients, but not in Taiwanese patients who achieved treatment-induced viral clearance. IFNL4 genotype was also associated with a decreased risk of cirrhosis (OR=0.66, 95%CI=0.46-0.93, P=0.018, in Taiwanese patients). We then engineered HepG2 cells to inducibly express IFN-λ4 in the presence or absence of interferon lambda receptor 1 (IFNLR1). Induction of IFN-λ4 resulted in its intracellular accumulation, mainly in lysosomes and late endosomes, and increased ER stress, leading to apoptosis and reduced proliferation. We identified the very-low-density lipoprotein receptor (VLDLR), which facilitates HCV entry into hepatocytes, as a transcript induced by IFN-λ4 but not IFN-λ3. Our results suggest that the molecular mechanisms underlying the anti-cirrhotic but pro-HCV associations observed for IFNL3/IFNL4 polymorphisms are, at least in part, contributed by intracellular accumulation of IFN-λ4 causing ER stress in hepatic cells.
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Affiliation(s)
- Olusegun O. Onabajo
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States
| | - Fang Wang
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States
| | - Mei-Hsuan Lee
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Oscar Florez-Vargas
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States
| | - Adeola Obajemu
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States
| | - Chizu Tanikawa
- Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Joselin M. Vargas
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States
| | - Shu-Fen Liao
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
| | - Ci Song
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yu-Han Huang
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chen-Yang Shen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - A. Rouf Banday
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States
| | - Thomas R. O’Brien
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, United States
| | - Zhibin Hu
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Koichi Matsuda
- Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Ludmila Prokunina-Olsson
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States
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47
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Hepatitis C Virus Protease Inhibitors Show Differential Efficacy and Interactions with Remdesivir for Treatment of SARS-CoV-2 In Vitro. Antimicrob Agents Chemother 2021; 65:e0268020. [PMID: 34097489 PMCID: PMC8370243 DOI: 10.1128/aac.02680-20] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Antivirals targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could improve treatment of COVID-19. We evaluated the efficacy of clinically relevant hepatitis C virus (HCV) NS3 protease inhibitors (PIs) against SARS-CoV-2 and their interactions with remdesivir, the only direct-acting antiviral approved for COVID-19 treatment. HCV PIs showed differential potency in short-term treatment assays based on the detection of SARS-CoV-2 spike protein in Vero E6 cells. Linear PIs boceprevir, telaprevir, and narlaprevir had 50% effective concentrations (EC50) of ∼40 μM. Among the macrocyclic PIs, simeprevir had the highest (EC50, 15 μM) and glecaprevir the lowest (EC50, >178 μM) potency, with paritaprevir, grazoprevir, voxilaprevir, vaniprevir, danoprevir, and deldeprevir in between. Acyclic PIs asunaprevir and faldaprevir had EC50s of 72 and 23 μM, respectively. ACH-806, inhibiting the HCV NS4A protease cofactor, had an EC50 of 46 μM. Similar and slightly increased PI potencies were found in human hepatoma Huh7.5 cells and human lung carcinoma A549-hACE2 cells, respectively. Selectivity indexes based on antiviral and cell viability assays were highest for linear PIs. In short-term treatments, combination of macrocyclic but not linear PIs with remdesivir showed synergism in Vero E6 and A549-hACE2 cells. Longer-term treatment of infected Vero E6 and A549-hACE2 cells with 1-fold EC50 PI revealed minor differences in the barrier to SARS-CoV-2 escape. Viral suppression was achieved with 3- to 8-fold EC50 boceprevir or 1-fold EC50 simeprevir or grazoprevir, but not boceprevir, in combination with 0.4- to 0.8-fold EC50 remdesivir; these concentrations did not lead to viral suppression in single treatments. This study could inform the development and application of protease inhibitors for optimized antiviral treatments of COVID-19.
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48
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A Novel Small Molecule Inhibits Hepatitis C Virus Propagation in Cell Culture. Microbiol Spectr 2021; 9:e0043921. [PMID: 34319169 PMCID: PMC8552720 DOI: 10.1128/spectrum.00439-21] [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] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Hepatitis C virus (HCV) can cause acute and chronic infection that is associated with considerable liver-related morbidity and mortality. In recent years, there has been a shift in the treatment paradigm with the discovery and approval of agents that target specific proteins vital for viral replication. We employed a cell culture-adapted strain of HCV and human hepatoma-derived cells lines to test the effects of our novel small-molecule compound (AO13) on HCV. Virus inhibition was tested by analyzing RNA replication, protein expression, and virus production in virus-infected cells treated with AO13. Treatment with AO13 inhibited virus spread in cell culture and showed a 100-fold reduction in the levels of infectious virus production. AO13 significantly reduced the level of viral RNA contained within cell culture fluids and reduced the cellular levels of HCV core protein, suggesting that the compound might act on a late step in the viral life cycle. Finally, we observed that AO13 did not affect the release of infectious virus from infected cells. Docking studies and molecular dynamics analyses suggested that AO13 might target the NS5B RNA polymerase, however, real-time RT-PCR analyses of cellular levels of HCV RNA showed only an ∼2-fold reduction in viral RNA levels in the presence of AO13. Taken together, this study revealed that AO13 showed consistent, but low-level antiviral effect against HCV, although the mechanism of action remains unclear. IMPORTANCE The discovery of curative antiviral drugs for a chronic disease such as HCV infection has encouraged drug discovery in the context of other viruses for which no curative drugs currently exist. Since we currently face a novel virus that has caused a pandemic, the need for new antiviral agents is more apparent than ever. We describe here a novel compound that shows a modest antiviral effect against HCV that could serve as a lead compound for future drug development against other important viruses such as SARS-CoV-2.
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49
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Elpek GO. Molecular pathways in viral hepatitis-associated liver carcinogenesis: An update. World J Clin Cases 2021; 9:4890-4917. [PMID: 34307543 PMCID: PMC8283590 DOI: 10.12998/wjcc.v9.i19.4890] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 03/14/2021] [Accepted: 05/26/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of cancer among primary malignant tumors of the liver and is a consequential cause of cancer-related deaths worldwide. In recent years, uncovering the molecular mechanisms involved in the development and behavior of this tumor has led to the identification of multiple potential treatment targets. Despite the vast amount of data on this topic, HCC remains a challenging tumor to treat due to its aggressive behavior and complex molecular profile. Therefore, the number of studies aiming to elucidate the mechanisms involved in both carcinogenesis and tumor progression in HCC continues to increase. In this context, the close association of HCC with viral hepatitis has led to numerous studies focusing on the direct or indirect involvement of viruses in the mechanisms contributing to tumor development and behavior. In line with these efforts, this review was undertaken to highlight the current understanding of the molecular mechanisms by which hepatitis B virus (HBV) and hepatitis C virus (HCV) participate in oncogenesis and tumor progression in HCC and summarize new findings. Cumulative evidence indicates that HBV DNA integration promotes genomic instability, resulting in the overexpression of genes related to cancer development, metastasis, and angiogenesis or inactivation of tumor suppressor genes. In addition, genetic variations in HBV itself, especially preS2 deletions, may play a role in malignant transformation. Epigenetic dysregulation caused by both viruses might also contribute to tumor formation and metastasis by modifying the methylation of DNA and histones or altering the expression of microRNAs. Similarly, viral proteins of both HBV and HCV can affect pathways that are important anticancer targets. The effects of these two viruses on the Hippo-Yap-Taz pathway in HCC development and behavior need to be investigated. Additional, comprehensive studies are also needed to determine these viruses' interaction with integrins, farnesoid X, and the apelin system in malignant transformation and tumor progression. Although the relationship of persistent inflammation caused by HBV and HCV hepatitis with carcinogenesis is well defined, further studies are warranted to decipher the relationship among inflammasomes and viruses in carcinogenesis and elucidate the role of virus-microbiota interactions in HCC development and progression.
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Affiliation(s)
- Gulsum Ozlem Elpek
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Turkey
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50
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Santana MS, Lopes R, Peron IH, Cruz CR, Gaspar AM, Costa PI. Natural Bioactive Compounds as Adjuvant Therapy for Hepatitis C Infection. CURRENT NUTRITION & FOOD SCIENCE 2021. [DOI: 10.2174/1573401316999201009152726] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Background:
Hepatitis C virus infection is a significant global health burden, which
causes acute or chronic hepatitis. Acute hepatitis C is generally asymptomatic and progresses to
cure, while persistent infection can progress to chronic liver disease and extrahepatic manifestations.
Standard treatment is expensive, poorly tolerated, and has variable sustained virologic responses
amongst the different viral genotypes. New therapies involve direct acting antivirals; however,
it is also very expensive and may not be accessible for all patients worldwide. In order to provide
a complementary approach to the already existing therapies, natural bioactive compounds are
investigated as to their several biologic activities, such as direct antiviral properties against hepatitis
C, and effects on mitigating chronic progression of the disease, which include hepatoprotective,
antioxidant, anticarcinogenic and anti-inflammatory activities; additionally, these compounds present
advantages, as chemical diversity, low cost of production and milder or inexistent side effects.
Objective:
To present a broad perspective on hepatitis C infection, the chronic disease, and natural
compounds with promising anti-HCV activity. Methods: This review consists of a systematic review
study about the natural bioactive compounds as a potential therapy for hepatitis C infection.
Results:
The quest for natural products has yielded compounds with biologic activity, including viral
replication inhibition in vitro, demonstrating antiviral activity against hepatitis C.
Conclusion:
One of the greatest advantages of using natural molecules from plant extracts is the
low cost of production, not requiring chemical synthesis, which can lead to less expensive therapies
available to low and middle-income countries.
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Affiliation(s)
- Moema S. Santana
- Food and Nutrition Department, School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara-SP, Brazil
| | - Rute Lopes
- Department of Biotechnology, Institute of Chemistry, Sao Paulo State University (UNESP), Araraquara-SP, Brazil
| | - Isabela H. Peron
- Food and Nutrition Department, School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara-SP, Brazil
| | - Carla R. Cruz
- Food and Nutrition Department, School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara-SP, Brazil
| | - Ana M.M. Gaspar
- Department of Biotechnology, Institute of Chemistry, São Paulo State University (UNESP), Araraquara-SP, Brazil
| | - Paulo I. Costa
- Food and Nutrition Department, School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara-SP, Brazil
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