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
| Autor: | Eva van der Veer, Amy K. Patick, Leen-Jan van Doorn, Søren Ottosen, Michael R. Hodges, Lu Yang, Anneke K. Raney, K. Zeh, Todd B. Parsley |
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| Rok vydání: | 2015 |
| Předmět: |
Macrocyclic Compounds
Pyrrolidines Hepacivirus Hepatitis C virus Oligonucleotides Thiophenes medicine.disease_cause Antiviral Agents Telaprevir chemistry.chemical_compound Serial passage Drug Resistance Viral medicine MiR-122 Humans Pharmacology (medical) Molecular Targeted Therapy NS5A NS5B Pharmacology biology Ribavirin Imidazoles virus diseases Valine Hepatitis C Chronic Cyclohexanols biology.organism_classification Virology digestive system diseases MicroRNAs Thiazoles Infectious Diseases chemistry Mutation Quinolines Drug Therapy Combination Replicon Carbamates 5' Untranslated Regions Oligopeptides medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 59:599-608 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.04220-14 |
| Popis: | Miravirsen is a β- d -oxy-locked nucleic acid-modified phosphorothioate antisense oligonucleotide targeting the liver-specific microRNA-122 (miR-122). Miravirsen demonstrated antiviral activity against hepatitis C virus (HCV) genotype 1b replicons with a mean 50% effective concentration (EC 50 ) of 0.67 μM. No cytotoxicity was observed up to the highest concentration tested (>320 μM) in different cell culture models, yielding a therapeutic index of ≥297. Combination studies of miravirsen with interferon α2b, ribavirin, and nonnucleoside (VX-222) and nucleoside (2′-methylcytidine) inhibitors of NS5B, NS5A (BMS-790052), or NS3 (telaprevir) indicated additive interactions. Miravirsen demonstrated broad antiviral activity when tested against HCV replicons resistant to NS3, NS5A, and NS5B inhibitors with less than 2-fold reductions in susceptibility. In serial passage studies, an A4C nucleotide change was observed in the HCV 5′ untranslated region (UTR) from cells passaged in the presence of up to 20 μM (40-fold the miravirsen EC 50 concentration) at day 72 of passage but not at earlier time points (up to 39 days of passage). Likewise, a C3U nucleotide change was observed in the HCV 5′UTR from subjects with viral rebound after the completion of therapy in a miravirsen phase 2 clinical trial. An HCV variant constructed to contain the A4C change was fully susceptible to miravirsen. A C3U HCV variant demonstrated overall reductions in susceptibility to miravirsen but was fully susceptible to all other anti-HCV agents tested. In summary, miravirsen has demonstrated broad antiviral activity and a relatively high genetic barrier to resistance. The identification of nucleotide changes associated with miravirsen resistance should help further elucidate the biology of miR-122 interactions with HCV. (The clinical trial study has been registered at ClinicalTrials.gov under registration no. NCT01200420). |
| Databáze: | OpenAIRE |
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