Selected replicon variants with low-level in vitro resistance to the hepatitis C virus NS5B polymerase inhibitor PSI-6130 lack cross-resistance with R1479.

Abstract

PSI-6130 (beta-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.

• Authors: Samir Ali, Vincent Leveque, Sophie Le Pogam, Han Ma, Friederike Philipp, Nicole Inocencio, Mark Smith, Andre Alker, Hyunsoon Kang, Isabel Najera, Klaus Klumpp, Julian Symons, Nick Cammack, Wen-Rong Jiang
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 52 Issue 12 Pg. 4356-69 (Dec 2008) ISSN: 1098-6596 [Electronic] United States
• PMID: 18838588 (Publication Type: Journal Article)

Chemical References

• Antiviral Agents
• Viral Nonstructural Proteins
• 2'-deoxy-2'-fluoro-2'-C-methylcytidine
• Deoxycytidine
• Cytidine
• NS-5 protein, hepatitis C virus
• RNA-Dependent RNA Polymerase
• 4'-azidocytidine

Topics

• Antiviral Agents (pharmacology)
• Cell Line
• Cytidine (analogs & derivatives, chemistry, pharmacology)
• Deoxycytidine (analogs & derivatives, chemistry, pharmacology)
• Drug Resistance, Viral (genetics)
• Genetic Variation
• Hepacivirus (drug effects, enzymology, genetics, physiology)
• Humans
• Molecular Sequence Data
• RNA-Dependent RNA Polymerase (antagonists & inhibitors)
• Replicon (drug effects, genetics)
• Sequence Analysis, DNA
• Viral Nonstructural Proteins (antagonists & inhibitors, genetics)