ArticleGastroenterology2014
Kinetic analyses reveal potent and early blockade of hepatitis C virus assembly by NS5A inhibitors.
Article in Gastroenterology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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Who cites it
61 citing papers in PubMed, 107 citations in OpenAlex.
- Utility of hepatitis C viral load monitoring on direct-acting antiviral therapy.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2015Trial
- A pharmacokinetic/viral kinetic model to evaluate the treatment effectiveness of danoprevir against chronic HCV.Antiviral therapy · 2015Trial
- Multiscale Modeling of an 8-Week Combination Regimen of Bemnifosbuvir and Ruzasvir in Patients with Chronic Hepatitis C Virus Infection.Clinical pharmacology and therapeutics · 2026Article
- Review
- Molecular characterization of the nonstructural 5A (NS5A) region of hepatitis C virus in Thai blood donors.Archives of microbiology · 2024Article
- Mathematical modeling of plus-strand RNA virus replication to identify broad-spectrum antiviral treatment strategies.PLoS computational biology · 2023Article
- NS5A domain I antagonises PKR to facilitate the assembly of infectious hepatitis C virus particles.PLoS pathogens · 2023Article
- Mathematical modeling of plus-strand RNA virus replication to identify broad-spectrum antiviral treatment strategies.bioRxiv : the preprint server for biology · 2022Article
- The Compound SBI-0090799 Inhibits Zika Virus Infection by BlockingJournal of virology · 2021Article
- The Role of RASs /RVs in the Current Management of HCV.Viruses · 2021Review
- Mechanistic Modeling of SARS-CoV-2 and Other Infectious Diseases and the Effects of Therapeutics.Clinical pharmacology and therapeutics · 2021Review
- A Small Molecule, 4-Phenylbutyric Acid, Suppresses HCV Replication via Epigenetically Induced Hepatic Hepcidin.International journal of molecular sciences · 2020Article
- Effect of P-body component Mov10 on HCV virus production and infectivity.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2020Article
- Hepatitis C Virus Replication.Cold Spring Harbor perspectives in medicine · 2020Review
- Effect of Low Positive End of Treatment Viral Load with Direct-Acting Antiviral Therapy on Sustained Virologic Response.Canadian journal of gastroenterology & hepatology · 2020Article
- Article
- Article
- Near-Neighbor Interactions in the NS3-4A Protease of HCV Impact Replicative Fitness of Drug-Resistant Viral Variants.Journal of molecular biology · 2019Article
- Hepatitis C virus cell culture models: an encomium on basic research paving the road to therapy development.Medical microbiology and immunology · 2019Review
- Overview of HCV Life Cycle with a Special Focus on Current and Possible Future Antiviral Targets.Viruses · 2019Review
1 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
BACKGROUND &
aimsAll-oral regimens combining different classes of direct-acting antivirals (DAA) are highly effective for treatment of patients with chronic hepatitis C. NS5A inhibitors will likely form a component of future interferon-sparing treatment regimens. However, despite their potential, the detailed mechanism of action of NS5A inhibitors is unclear. To study their mechanisms, we compared their kinetics of antiviral suppression with those of other classes of DAA, using the hepatitis C virus genotype 1a cell culture-infectious virus H77S.3.
methodsWe performed detailed kinetic analyses of specific steps in the hepatitis C virus life cycle using cell cultures incubated with protease inhibitors, polymerase inhibitors, or NS5A inhibitors. Assays were designed to measure active viral RNA synthesis and steady-state RNA abundance, polyprotein synthesis, virion assembly, and infectious virus production.
resultsDespite their high potency, NS5A inhibitors were slow to inhibit viral RNA synthesis compared with protease or polymerase inhibitors. By 24 hours after addition of an NS5A inhibitor, polyprotein synthesis was reduced <50%, even at micromolar concentrations. In contrast, inhibition of virus release by NS5A inhibitors was potent and rapid, with onset of inhibition as early as 2 hours. Cells incubated with NS5A inhibitors were rapidly depleted of intracellular infectious virus and RNA-containing hepatitis C virus particles, indicating a block in virus assembly.
conclusionsDAAs that target NS5A rapidly inhibit intracellular assembly of genotype 1a virions. They also inhibit formation of functional replicase complexes, but have no activity against preformed replicase, thereby resulting in slow shut-off of viral RNA synthesis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.