Selected Replicon Variants with Low-Level In Vitro Resistance to the Hepatitis C Virus NS5B Polymerase Inhibitor PSI-6130 Lack Cross-Resistance with R1479
| Autor: | Isabel Najera, Friederike Philipp, Han Ma, Wen-Rong Jiang, Mark D. Smith, André Alker, Samir Ali, Nick Cammack, Nicole Inocencio, Klaus Klumpp, Vincent Leveque, Sophie Le Pogam, Julian Symons, Hyunsoon Kang |
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| Rok vydání: | 2008 |
| Předmět: |
PSI-6130
Hepatitis C virus Molecular Sequence Data RNA-dependent RNA polymerase Cytidine Hepacivirus Viral Nonstructural Proteins medicine.disease_cause Antiviral Agents Deoxycytidine Virus Cell Line chemistry.chemical_compound Drug Resistance Viral medicine Humans Pharmacology (medical) Replicon NS5B Polymerase Pharmacology biology Genetic Variation Sequence Analysis DNA RNA-Dependent RNA Polymerase Virology Molecular biology Infectious Diseases chemistry biology.protein Mericitabine |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 52:4356-4369 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.00444-08 |
| Popis: | PSI-6130 (β- d -2′-deoxy-2′-fluoro-2′- C -methylcytidine) is a selective inhibitor of hepatitis C virus (HCV) replication that targets the NS5B polymerase. R7128, the prodrug of PSI-6130, has shown antiviral efficacy in patients chronically infected with HCV genotype 1a (GT-1a) and GT-1b. We observed that the compound exhibited potent in vitro activity against laboratory-optimized HCV replicons as well as against a panel of replicons containing NS5B HCV polymerases derived from GT-1a and GT-1b clinical isolates. We used the HCV replicon cell system to examine the emergence of variants with reduced sensitivity to PSI-6130. Short-term treatment of cells harboring the HCV subgenomic replicon with PSI-6130 cleared the replicon without generating resistant variants. Long-term culture of the cells under the compound selection generated the S282T substitution in a complex pattern with other amino acid substitutions in the NS5B polymerase. The presence of the coselected substitutions did not increase the moderate three- to sixfold loss of sensitivity to PSI-6130 mediated by the S282T substitution; however, their presence enhanced the replication capacity compared to the replication levels seen with the S282T substitution alone. We also observed a lack of cross-resistance between PSI-6130 and R1479 and demonstrated that long-term culture selection with PSI-6130 in replicon cells harboring preexisting mutations resistant to R1479 (S96T/N142T) results in the emergence of the S282T substitution and the reversion of S96T to wild-type serine. In conclusion, PSI-6130 presents a high barrier to resistance selection in vitro, selects for variants exhibiting only low-level resistance, and lacks cross-resistance with R1479, supporting the continued development of the prodrug R7128 as a therapeutic agent for the treatment of HCV infection. |
| Databáze: | OpenAIRE |
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