title: Inhibition of hepatitis C virus replicon RNA synthesis by PSI-352938, a cyclic phosphate prodrug of β-D-2'-deoxy-2'-α-fluoro-2'-β-C-methylguanosine.
abstract: PSI-352938 is a novel cyclic phosphate prodrug of β-D-2'-deoxy-2'-α-fluoro-2'-β-C-methylguanosine 5'-monophosphate that has potent activity against hepatitis C virus (HCV) in vitro. The studies described here characterize the in vitro anti-HCV activity of PSI-352938, alone and in combination with other inhibitors of HCV, and the cross-resistance profile of PSI-352938. The effective concentration required to achieve 50% inhibition for PSI-352938, determined using genotype 1a-, 1b-, and 2a-derived replicons stably expressed in the Lunet cell line, were 0.20, 0.13, and 0.14 μM, respectively. The active 5'-triphosphate metabolite, PSI-352666, inhibited recombinant NS5B polymerase from genotypes 1 to 4 with comparable 50% inhibitory concentrations. In contrast, PSI-352938 did not inhibit the replication of hepatitis B virus or human immunodeficiency virus in vitro. PSI-352666 did not significantly affect the activity of human DNA and RNA polymerases. PSI-352938 and its cyclic phosphate metabolites did not affect the cyclic GMP-mediated activation of protein kinase G. Clearance studies using replicon cells demonstrated that PSI-352938 cleared cells of HCV replicon RNA and prevented replicon rebound. An additive to synergistic effect was observed when PSI-352938 was combined with other classes of HCV inhibitors, including alpha interferon, ribavirin, NS3/4A inhibitors, an NS5A inhibitor, and nucleoside/nucleotide and nonnucleoside inhibitors. Cross-resistance studies showed that PSI-352938 remained fully active against replicons containing the S282T or the S96T/N142T amino acid alteration. Replicons that contain mutations conferring resistance to various classes of nonnucleoside inhibitors also remained sensitive to inhibition by PSI-352938. PSI-352938 is currently being evaluated in a phase I clinical study in genotype 1-infected individuals.
authors: Pharmasset, Inc., 303A College Road East, Princeton, NJ 08540, USA. alam@pharmasset.com
authors: Angela M
authors: AM
authors: Lam
authors: Christine
authors: C
authors: Espiritu
authors: Eisuke
authors: E
authors: Murakami
authors: Veronique
authors: V
authors: Zennou
authors: Shalini
authors: S
authors: Bansal
authors: Holly M
authors: HM
authors: Micolochick Steuer
authors: Congrong
authors: C
authors: Niu
authors: Meg
authors: M
authors: Keilman
authors: Haiying
authors: H
authors: Bao
authors: Nigel
authors: N
authors: Bourne
authors: Ronald L
authors: RL
authors: Veselenak
authors: P Ganapati
authors: PG
authors: Reddy
authors: Wonsuk
authors: W
authors: Chang
authors: Jinfa
authors: J
authors: Du
authors: Dhanapalan
authors: D
authors: Nagarathnam
authors: Michael J
authors: MJ
authors: Sofia
authors: Michael J
authors: MJ
authors: Otto
authors: Phillip A
authors: PA
authors: Furman
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D003498:Cyclic P-Oxides / Q000494:pharmacology*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D024882:Drug Resistance, Viral; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D009705:Nucleosides / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology*; D012367:RNA, Viral / Q000096:biosynthesis*; D012093:Replicon / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D003498:Cyclic P-Oxides; D009705:Nucleosides; C556498:PSI 352938; D011355:Prodrugs; D012367:RNA, Viral; C560850:beta-D-2'-deoxy-2'-alpha-fluoro-2'-beta-C-methylguanosine; D003849:Deoxyguanosine