Activity and the metabolic activation pathway of the potent and selective hepatitis C virus pronucleotide inhibitor PSI-353661

Phillip A. Furman, Eisuke Murakami, Congrong Niu, Angela M. Lam, Christine Espiritu, Shalini Bansal, Haiying Bao, Tatiana Tolstykh, Holly Micolochick Steuer, Meg Keilman, Veronique Zennou, Nigel Bourne, Ronald L. Veselenak, Wonsuk Chang, Bruce S. Ross, Jinfa Du, Michael J. Otto, Michael J. Sofia

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

PSI-353661, a phosphoramidate prodrug of 2′-deoxy-2′-fluoro-2′-C-methylguanosine-5′-monophosphate, is a highly active inhibitor of genotype 1a, 1b, and 2a HCV RNA replication in the replicon assay and of genotype 1a and 2a infectious virus replication. PSI-353661 is active against replicons harboring the NS5B S282T or S96T/N142T amino acid alterations that confer decreased susceptibility to nucleoside/tide analogs as well as mutations that confer resistance to non-nucleoside inhibitors of NS5B. Replicon clearance studies show that PSI-353661 was able to clear cells of HCV replicon RNA and prevent a rebound in replicon RNA. PSI-353661 showed no toxicity toward bone marrow stem cells or mitochondrial toxicity. The metabolism to the active 5′-triphosphate involves hydrolysis of the carboxyl ester by cathepsin A (Cat A) and carboxylesterase 1 (CES1) followed by a putative nucleophilic attack on the phosphorus by the carboxyl group resulting in the elimination of phenol and the alaninyl phosphate metabolite, PSI-353131. Histidine triad nucleotide-binding protein 1 (Hint 1) then removes the amino acid moiety, which is followed by hydrolysis of the methoxyl group at the O6-position of the guanine base by adenosine deaminase-like protein 1 (ADAL1) to give 2′-deoxy-2′-fluoro-2′-C-methylguanosine-5′-monophosphate. The monophosphate is phosphorylated to the diphosphate by guanylate kinase. Nucleoside diphosphate kinase is the primary enzyme involved in phosphorylation of the diphosphate to the active triphosphate, PSI-352666. PSI-352666 is equally active against wild-type NS5B and NS5B containing the S282T amino acid alteration.

Original languageEnglish (US)
Pages (from-to)120-132
Number of pages13
JournalAntiviral research
Volume91
Issue number2
DOIs
StatePublished - Aug 2011

Keywords

  • 2′-Deoxy-2′-fluoro-2′-C-methylguanosine-5′-monophosphate
  • Antiviral
  • Hepatitis C virus
  • Nucleotide analog
  • Phosphoramidate
  • Prodrug

ASJC Scopus subject areas

  • Pharmacology
  • Virology

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    Furman, P. A., Murakami, E., Niu, C., Lam, A. M., Espiritu, C., Bansal, S., Bao, H., Tolstykh, T., Micolochick Steuer, H., Keilman, M., Zennou, V., Bourne, N., Veselenak, R. L., Chang, W., Ross, B. S., Du, J., Otto, M. J., & Sofia, M. J. (2011). Activity and the metabolic activation pathway of the potent and selective hepatitis C virus pronucleotide inhibitor PSI-353661. Antiviral research, 91(2), 120-132. https://doi.org/10.1016/j.antiviral.2011.05.003