ArticlePloS one2010
DEB025 (Alisporivir) inhibits hepatitis C virus replication by preventing a cyclophilin A induced cis-trans isomerisation in domain II of NS5A.
Article in PloS one, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 100 papers.
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Who cites it
100 citing papers in PubMed, 181 citations in OpenAlex.
- In vitro antiviral activity and preclinical and clinical resistance profile of miravirsen, a novel anti-hepatitis C virus therapeutic targeting the human factor miR-122.Antimicrobial agents and chemotherapy · 2015Trial
- Towards broader-spectrum direct-acting antivirals against RNA viruses.Nature reviews. Microbiology · 2026Review
- Structural and Kinetic Variability of Pathogen Cyclophilins: Functional Diversification and Therapeutic Potential.ACS infectious diseases · 2026Review
- Development of a Norway rat hepacivirus reporter for high-throughput quantification of neutralizing antibodies.Journal of virology · 2026Article
- Identification and characterization of a nonpeptidic cyclophilin ligand with antiviral activity against feline and porcine α-coronaviruses.Veterinary research · 2025Article
- DR5 Disulfide Bonding Functions as a Sensor and Effector of Protein Folding Stress.Molecular cancer research : MCR · 2025Article
- Cyclophilin A: promising target in cancer therapy.Cancer biology & therapy · 2024Review
- Article
- Detection of Hepatitis C Virus Infection from Patient Sera in Cell Culture Using Semi-Automated Image Analysis.Viruses · 2024Article
- Evaluating the potential of non-immunosuppressive cyclosporin analogs for targeting Toxoplasma gondii cyclophilin: Insights from structural studies.Protein science : a publication of the Protein Society · 2024Article
- Cyclophilin inhibition as a strategy for the treatment of human disease.Frontiers in pharmacology · 2024Review
- The Cyclophilin Inhibitor Rencofilstat Decreases HCV-Induced Hepatocellular Carcinoma Independently of Its Antiviral Activity.Viruses · 2023Article
- Viral Evolution Shaped by Host Proteostasis Networks.Annual review of virology · 2023Review
- Viral RNA Is a Hub for Critical Host-Virus Interactions.Sub-cellular biochemistry · 2023Article
- Non-Immunosuppressive Cyclophilin Inhibitors.Angewandte Chemie (International ed. in English) · 2022Review
- Structure-function analysis of enterovirus protease 2A in complex with its essential host factor SETD3.Nature communications · 2022Article
- Repurposing of cyclophilin A inhibitors as broad-spectrum antiviral agents.Drug discovery today · 2022Review
- Cyclophilins and Their Roles in Hepatitis C Virus and Flavivirus Infections: Perspectives for Novel Antiviral Approaches.Pathogens (Basel, Switzerland) · 2021Review
- Article
- ISGylation of Hepatitis C Virus NS5A Protein Promotes Viral RNA Replication via Recruitment of Cyclophilin A.Journal of virology · 2020Article
40 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
15 authors at 6 institutions in 5 countries.
Funding
Abstract
DEB025/Debio 025 (Alisporivir) is a cyclophilin (Cyp)-binding molecule with potent anti-hepatitis C virus (HCV) activity both in vitro and in vivo. It is currently being evaluated in phase II clinical trials. DEB025 binds to CypA, a peptidyl-prolyl cis-trans isomerase which is a crucial cofactor for HCV replication. Here we report that it was very difficult to select resistant replicons (genotype 1b) to DEB025, requiring an average of 20 weeks (four independent experiments), compared to the typically <2 weeks with protease or polymerase inhibitors. This indicates a high genetic barrier to resistance for DEB025. Mutation D320E in NS5A was the only mutation consistently selected in the replicon genome. This mutation alone conferred a low-level (3.9-fold) resistance. Replacing the NS5A gene (but not the NS5B gene) from the wild type (WT) genome with the corresponding sequence from the DEB025(res) replicon resulted in transfer of resistance. Cross-resistance with cyclosporine A (CsA) was observed, whereas NS3 protease and NS5B polymerase inhibitors retained WT-activity against DEB025(res) replicons. Unlike WT, DEB025(res) replicon replicated efficiently in CypA knock down cells. However, DEB025 disrupted the interaction between CypA and NS5A regardless of whether the NS5A protein was derived from WT or DEB025(res) replicon. NMR titration experiments with peptides derived from the WT or the DEB025(res) domain II of NS5A corroborated this observation in a quantitative manner. Interestingly, comparative NMR studies on two 20-mer NS5A peptides that contain D320 or E320 revealed a shift in population between the major and minor conformers. These data suggest that D320E conferred low-level resistance to DEB025 probably by reducing the need for CypA-dependent isomerisation of NS5A. Prolonged DEB025 treatment and multiple genotypic changes may be necessary to generate significant resistance to DEB025, underlying the high barrier to 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.