ArticleAntimicrobial agents and chemotherapy2010
Mechanism of resistance of hepatitis C virus replicons to structurally distinct cyclophilin inhibitors.
Article in Antimicrobial agents and chemotherapy, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 73 citations in OpenAlex.
- Cyclophilin A: promising target in cancer therapy.Cancer biology & therapy · 2024Review
- Repurposing of cyclophilin A inhibitors as broad-spectrum antiviral agents.Drug discovery today · 2022Review
- Host-Directed Antiviral Therapy.Clinical microbiology reviews · 2020Review
- Alisporivir inhibits MERS- and SARS-coronavirus replication in cell culture, but not SARS-coronavirus infection in a mouse model.Virus research · 2017Article
- My Cousin, My Enemy: quasispecies suppression of drug resistance.Current opinion in virology · 2016Review
- Discovery, Optimization, and Characterization of Novel Chlorcyclizine Derivatives for the Treatment of Hepatitis C Virus Infection.Journal of medicinal chemistry · 2016Article
- Chaperones in hepatitis C virus infection.World journal of hepatology · 2016Review
- Article
- Review
- The role of immunophilins in viral infection.Biochimica et biophysica acta · 2015Article
- Increased replicative fitness can lead to decreased drug sensitivity of hepatitis C virus.Journal of virology · 2014Article
- What are the pros and cons of the use of host-targeted agents against hepatitis C?Antiviral research · 2014Article
- Cyclophilin A as a New Therapeutic Target for Hepatitis C Virus-induced Hepatocellular Carcinoma.The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology · 2013Review
- Cyclophilins as modulators of viral replication.Viruses · 2013Review
- Current and emerging antiviral treatments for hepatitis C infection.British journal of clinical pharmacology · 2013Review
- Phenotypic analysis of NS5A variant from liver transplant patient with increased cyclosporine susceptibility.Virology · 2013Article
- Cyclophilin inhibitors block arterivirus replication by interfering with viral RNA synthesis.Journal of virology · 2013Article
- Is there a role for cyclophilin inhibitors in the management of primary biliary cirrhosis?Viruses · 2013Review
- Hepatitis C virus NS5B and host cyclophilin A share a common binding site on NS5A.The Journal of biological chemistry · 2012Article
- Article
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The current standard of care for hepatitis C virus (HCV) infection, pegylated alpha interferon in combination with ribavirin, has a limited response rate and adverse side effects. Drugs targeting viral proteins are in clinical development, but they suffer from the development of high viral resistance. The inhibition of cellular proteins that are essential for viral amplification is thought to have a higher barrier to the emergence of resistance. Three cyclophilin inhibitors, the cyclosporine analogs DEBIO-025, SCY635, and NIM811, have shown promising results for the treatment of HCV infection in early clinical trials. In this study, we investigated the frequency and mechanism of resistance to cyclosporine (CsA), NIM811, and a structurally unrelated cyclophilin inhibitor, SFA-1, in replicon-containing Huh7 cells. Cross-resistance between all clones was observed. NIM811-resistant clones were selected only after obtaining initial resistance to either CsA or SFA-1. The time required to select resistance against cyclophilin inhibitors was significantly longer than that required for resistance selection against viral protein inhibitors, and the achievable resistance level was substantially lower. Resistance to cyclophilin inhibitors was mediated by amino acid substitutions in NS3, NS5A, and NS5B, with NS5A mutations conferring the majority of resistance. Mutation D320E in NS5A mediated most of the resistance conferred by NS5A. Taken together, the results indicate that there is a very low frequency and level of resistance to cyclophilin-binding drugs mediated by amino acid substitutions in three viral proteins. The interaction of cyclophilin with NS5A seems to be the most critical, since the NS5A mutations have the largest impact on resistance.
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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.