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

Angela M. Lam, Christine Espiritu, Eisuke Murakami, Veronique Zennou, Shalini Bansal, Holly M. Micolochick Steuer, Congrong Niu, Meg Keilman, Haiying Bao, Nigel Bourne, Ronald L. Veselenak, P. Ganapati Reddy, Wonsuk Chang, Jinfa Du, Dhanapalan Nagarathnam, Michael J. Sofia, Michael J. Otto, Phillip A. Furman

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2566-2575
Number of pages10
JournalAntimicrobial Agents and Chemotherapy
Volume55
Issue number6
DOIs
StatePublished - Jun 2011

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Replicon
Prodrugs
Hepacivirus
Phosphates
RNA
Genotype
PSI 352938
7-methylguanosine
Cyclic GMP-Dependent Protein Kinases
Ribavirin
Cyclic GMP
DNA-Directed DNA Polymerase
DNA-Directed RNA Polymerases
Nucleosides
Hepatitis B virus
Interferon-alpha
Human Activities
Inhibitory Concentration 50
Nucleotides
HIV

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

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. / Lam, Angela M.; Espiritu, Christine; Murakami, Eisuke; Zennou, Veronique; Bansal, Shalini; Micolochick Steuer, Holly M.; Niu, Congrong; Keilman, Meg; Bao, Haiying; Bourne, Nigel; Veselenak, Ronald L.; Reddy, P. Ganapati; Chang, Wonsuk; Du, Jinfa; Nagarathnam, Dhanapalan; Sofia, Michael J.; Otto, Michael J.; Furman, Phillip A.

In: Antimicrobial Agents and Chemotherapy, Vol. 55, No. 6, 06.2011, p. 2566-2575.

Research output: Contribution to journalArticle

Lam, AM, Espiritu, C, Murakami, E, Zennou, V, Bansal, S, Micolochick Steuer, HM, Niu, C, Keilman, M, Bao, H, Bourne, N, Veselenak, RL, Reddy, PG, Chang, W, Du, J, Nagarathnam, D, Sofia, MJ, Otto, MJ & Furman, PA 2011, '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', Antimicrobial Agents and Chemotherapy, vol. 55, no. 6, pp. 2566-2575. https://doi.org/10.1128/AAC.00032-11
Lam, Angela M. ; Espiritu, Christine ; Murakami, Eisuke ; Zennou, Veronique ; Bansal, Shalini ; Micolochick Steuer, Holly M. ; Niu, Congrong ; Keilman, Meg ; Bao, Haiying ; Bourne, Nigel ; Veselenak, Ronald L. ; Reddy, P. Ganapati ; Chang, Wonsuk ; Du, Jinfa ; Nagarathnam, Dhanapalan ; Sofia, Michael J. ; Otto, Michael J. ; Furman, Phillip A. / 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. In: Antimicrobial Agents and Chemotherapy. 2011 ; Vol. 55, No. 6. pp. 2566-2575.
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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.",
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AU - Murakami, Eisuke

AU - Zennou, Veronique

AU - Bansal, Shalini

AU - Micolochick Steuer, Holly M.

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AU - Bao, Haiying

AU - Bourne, Nigel

AU - Veselenak, Ronald L.

AU - Reddy, P. Ganapati

AU - Chang, Wonsuk

AU - Du, Jinfa

AU - Nagarathnam, Dhanapalan

AU - Sofia, Michael J.

AU - Otto, Michael J.

AU - Furman, Phillip A.

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