PSI-7851, a pronucleotide of β-D-2′-deoxy-2′-fluoro- 2′-C-methyluridine monophosphate, is a potent and pan-genotype inhibitor of hepatitis C virus replication

Angela M. Lam, Eisuke Murakami, Christine Espiritu, Holly M. Micolochick Steuer, Congrong Niu, Meg Keilman, Haiying Bao, Veronique Zennou, Nigel Bourne, Justin G. Julander, John D. Morrey, Donald F. Smee, David N. Frick, Julie A. Heck, Peiyuan Wang, Dhanapalan Nagarathnam, Bruce S. Ross, Michael J. Sofia, Michael J. Otto, Phillip A. Furman

Research output: Contribution to journalArticle

107 Citations (Scopus)

Abstract

The hepatitis C virus (HCV) NS5B RNA polymerase facilitates the RNA synthesis step during the HCV replication cycle. Nucleoside analogs targeting the NS5B provide an attractive approach to treating HCV infections because of their high barrier to resistance and pan-genotype activity. PSI-7851, a pronucleotide of β-D-2′-deoxy-2′-fluoro-2′-C- methyluridine-5′-monophosphate, is a highly active nucleotide analog inhibitor of HCV for which a phase 1b multiple ascending dose study of genotype 1-infected individuals was recently completed (M. Rodriguez-Torres, E. Lawitz, S. Flach, J. M. Denning, E. Albanis, W. T. Symonds, and M. M. Berry, Abstr. 60th Annu. Meet. Am. Assoc. Study Liver Dis., abstr. LB17, 2009). The studies described here characterize the in vitro antiviral activity and cytotoxicity profile of PSI-7851. The 50% effective concentration for PSI-7851 against the genotype 1b replicon was determined to be 0.075 ± 0.050 μM (mean ± standard deviation). PSI-7851 was similarly effective against replicons derived from genotypes 1a, 1b, and 2a and the genotype 1a and 2a infectious virus systems. The active triphosphate, PSI-7409, inhibited recombinant NS5B polymerases from genotypes 1 to 4 with comparable 50% inhibitory concentrations. PSI-7851 is a specific HCV inhibitor, as it lacks antiviral activity against other closely related and unrelated viruses. PSI-7409 also lacked any significant activity against cellular DNA and RNA polymerases. No cytotoxicity, mitochondrial toxicity, or bone marrow toxicity was associated with PSI-7851 at the highest concentration tested (100 μM). Crossresistance studies using replicon mutants conferring resistance to modified nucleoside analogs showed that PSI-7851 was less active against the S282T replicon mutant, whereas cells expressing a replicon containing the S96T/N142T mutation remained fully susceptible to PSI-7851. Clearance studies using replicon cells demonstrated that PSI-7851 was able to clear cells of HCV replicon RNA and prevent viral rebound.

Original languageEnglish (US)
Pages (from-to)3187-3196
Number of pages10
JournalAntimicrobial Agents and Chemotherapy
Volume54
Issue number8
DOIs
StatePublished - Aug 1 2010

Fingerprint

Replicon
Virus Replication
Hepacivirus
Genotype
DNA-Directed RNA Polymerases
Nucleosides
Antiviral Agents
Viruses
Viral RNA
Virus Diseases
DNA-Directed DNA Polymerase
2'-C-methyluridine
Inhibitory Concentration 50
Nucleotides
Bone Marrow
RNA
Mutation
Liver

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

PSI-7851, a pronucleotide of β-D-2′-deoxy-2′-fluoro- 2′-C-methyluridine monophosphate, is a potent and pan-genotype inhibitor of hepatitis C virus replication. / Lam, Angela M.; Murakami, Eisuke; Espiritu, Christine; Micolochick Steuer, Holly M.; Niu, Congrong; Keilman, Meg; Bao, Haiying; Zennou, Veronique; Bourne, Nigel; Julander, Justin G.; Morrey, John D.; Smee, Donald F.; Frick, David N.; Heck, Julie A.; Wang, Peiyuan; Nagarathnam, Dhanapalan; Ross, Bruce S.; Sofia, Michael J.; Otto, Michael J.; Furman, Phillip A.

In: Antimicrobial Agents and Chemotherapy, Vol. 54, No. 8, 01.08.2010, p. 3187-3196.

Research output: Contribution to journalArticle

Lam, AM, Murakami, E, Espiritu, C, Micolochick Steuer, HM, Niu, C, Keilman, M, Bao, H, Zennou, V, Bourne, N, Julander, JG, Morrey, JD, Smee, DF, Frick, DN, Heck, JA, Wang, P, Nagarathnam, D, Ross, BS, Sofia, MJ, Otto, MJ & Furman, PA 2010, 'PSI-7851, a pronucleotide of β-D-2′-deoxy-2′-fluoro- 2′-C-methyluridine monophosphate, is a potent and pan-genotype inhibitor of hepatitis C virus replication', Antimicrobial Agents and Chemotherapy, vol. 54, no. 8, pp. 3187-3196. https://doi.org/10.1128/AAC.00399-10
Lam, Angela M. ; Murakami, Eisuke ; Espiritu, Christine ; Micolochick Steuer, Holly M. ; Niu, Congrong ; Keilman, Meg ; Bao, Haiying ; Zennou, Veronique ; Bourne, Nigel ; Julander, Justin G. ; Morrey, John D. ; Smee, Donald F. ; Frick, David N. ; Heck, Julie A. ; Wang, Peiyuan ; Nagarathnam, Dhanapalan ; Ross, Bruce S. ; Sofia, Michael J. ; Otto, Michael J. ; Furman, Phillip A. / PSI-7851, a pronucleotide of β-D-2′-deoxy-2′-fluoro- 2′-C-methyluridine monophosphate, is a potent and pan-genotype inhibitor of hepatitis C virus replication. In: Antimicrobial Agents and Chemotherapy. 2010 ; Vol. 54, No. 8. pp. 3187-3196.
@article{a37f01765f75490cb9f856a7b3a5b493,
title = "PSI-7851, a pronucleotide of β-D-2′-deoxy-2′-fluoro- 2′-C-methyluridine monophosphate, is a potent and pan-genotype inhibitor of hepatitis C virus replication",
abstract = "The hepatitis C virus (HCV) NS5B RNA polymerase facilitates the RNA synthesis step during the HCV replication cycle. Nucleoside analogs targeting the NS5B provide an attractive approach to treating HCV infections because of their high barrier to resistance and pan-genotype activity. PSI-7851, a pronucleotide of β-D-2′-deoxy-2′-fluoro-2′-C- methyluridine-5′-monophosphate, is a highly active nucleotide analog inhibitor of HCV for which a phase 1b multiple ascending dose study of genotype 1-infected individuals was recently completed (M. Rodriguez-Torres, E. Lawitz, S. Flach, J. M. Denning, E. Albanis, W. T. Symonds, and M. M. Berry, Abstr. 60th Annu. Meet. Am. Assoc. Study Liver Dis., abstr. LB17, 2009). The studies described here characterize the in vitro antiviral activity and cytotoxicity profile of PSI-7851. The 50{\%} effective concentration for PSI-7851 against the genotype 1b replicon was determined to be 0.075 ± 0.050 μM (mean ± standard deviation). PSI-7851 was similarly effective against replicons derived from genotypes 1a, 1b, and 2a and the genotype 1a and 2a infectious virus systems. The active triphosphate, PSI-7409, inhibited recombinant NS5B polymerases from genotypes 1 to 4 with comparable 50{\%} inhibitory concentrations. PSI-7851 is a specific HCV inhibitor, as it lacks antiviral activity against other closely related and unrelated viruses. PSI-7409 also lacked any significant activity against cellular DNA and RNA polymerases. No cytotoxicity, mitochondrial toxicity, or bone marrow toxicity was associated with PSI-7851 at the highest concentration tested (100 μM). Crossresistance studies using replicon mutants conferring resistance to modified nucleoside analogs showed that PSI-7851 was less active against the S282T replicon mutant, whereas cells expressing a replicon containing the S96T/N142T mutation remained fully susceptible to PSI-7851. Clearance studies using replicon cells demonstrated that PSI-7851 was able to clear cells of HCV replicon RNA and prevent viral rebound.",
author = "Lam, {Angela M.} and Eisuke Murakami and Christine Espiritu and {Micolochick Steuer}, {Holly M.} and Congrong Niu and Meg Keilman and Haiying Bao and Veronique Zennou and Nigel Bourne and Julander, {Justin G.} and Morrey, {John D.} and Smee, {Donald F.} and Frick, {David N.} and Heck, {Julie A.} and Peiyuan Wang and Dhanapalan Nagarathnam and Ross, {Bruce S.} and Sofia, {Michael J.} and Otto, {Michael J.} and Furman, {Phillip A.}",
year = "2010",
month = "8",
day = "1",
doi = "10.1128/AAC.00399-10",
language = "English (US)",
volume = "54",
pages = "3187--3196",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "8",

}

TY - JOUR

T1 - PSI-7851, a pronucleotide of β-D-2′-deoxy-2′-fluoro- 2′-C-methyluridine monophosphate, is a potent and pan-genotype inhibitor of hepatitis C virus replication

AU - Lam, Angela M.

AU - Murakami, Eisuke

AU - Espiritu, Christine

AU - Micolochick Steuer, Holly M.

AU - Niu, Congrong

AU - Keilman, Meg

AU - Bao, Haiying

AU - Zennou, Veronique

AU - Bourne, Nigel

AU - Julander, Justin G.

AU - Morrey, John D.

AU - Smee, Donald F.

AU - Frick, David N.

AU - Heck, Julie A.

AU - Wang, Peiyuan

AU - Nagarathnam, Dhanapalan

AU - Ross, Bruce S.

AU - Sofia, Michael J.

AU - Otto, Michael J.

AU - Furman, Phillip A.

PY - 2010/8/1

Y1 - 2010/8/1

N2 - The hepatitis C virus (HCV) NS5B RNA polymerase facilitates the RNA synthesis step during the HCV replication cycle. Nucleoside analogs targeting the NS5B provide an attractive approach to treating HCV infections because of their high barrier to resistance and pan-genotype activity. PSI-7851, a pronucleotide of β-D-2′-deoxy-2′-fluoro-2′-C- methyluridine-5′-monophosphate, is a highly active nucleotide analog inhibitor of HCV for which a phase 1b multiple ascending dose study of genotype 1-infected individuals was recently completed (M. Rodriguez-Torres, E. Lawitz, S. Flach, J. M. Denning, E. Albanis, W. T. Symonds, and M. M. Berry, Abstr. 60th Annu. Meet. Am. Assoc. Study Liver Dis., abstr. LB17, 2009). The studies described here characterize the in vitro antiviral activity and cytotoxicity profile of PSI-7851. The 50% effective concentration for PSI-7851 against the genotype 1b replicon was determined to be 0.075 ± 0.050 μM (mean ± standard deviation). PSI-7851 was similarly effective against replicons derived from genotypes 1a, 1b, and 2a and the genotype 1a and 2a infectious virus systems. The active triphosphate, PSI-7409, inhibited recombinant NS5B polymerases from genotypes 1 to 4 with comparable 50% inhibitory concentrations. PSI-7851 is a specific HCV inhibitor, as it lacks antiviral activity against other closely related and unrelated viruses. PSI-7409 also lacked any significant activity against cellular DNA and RNA polymerases. No cytotoxicity, mitochondrial toxicity, or bone marrow toxicity was associated with PSI-7851 at the highest concentration tested (100 μM). Crossresistance studies using replicon mutants conferring resistance to modified nucleoside analogs showed that PSI-7851 was less active against the S282T replicon mutant, whereas cells expressing a replicon containing the S96T/N142T mutation remained fully susceptible to PSI-7851. Clearance studies using replicon cells demonstrated that PSI-7851 was able to clear cells of HCV replicon RNA and prevent viral rebound.

AB - The hepatitis C virus (HCV) NS5B RNA polymerase facilitates the RNA synthesis step during the HCV replication cycle. Nucleoside analogs targeting the NS5B provide an attractive approach to treating HCV infections because of their high barrier to resistance and pan-genotype activity. PSI-7851, a pronucleotide of β-D-2′-deoxy-2′-fluoro-2′-C- methyluridine-5′-monophosphate, is a highly active nucleotide analog inhibitor of HCV for which a phase 1b multiple ascending dose study of genotype 1-infected individuals was recently completed (M. Rodriguez-Torres, E. Lawitz, S. Flach, J. M. Denning, E. Albanis, W. T. Symonds, and M. M. Berry, Abstr. 60th Annu. Meet. Am. Assoc. Study Liver Dis., abstr. LB17, 2009). The studies described here characterize the in vitro antiviral activity and cytotoxicity profile of PSI-7851. The 50% effective concentration for PSI-7851 against the genotype 1b replicon was determined to be 0.075 ± 0.050 μM (mean ± standard deviation). PSI-7851 was similarly effective against replicons derived from genotypes 1a, 1b, and 2a and the genotype 1a and 2a infectious virus systems. The active triphosphate, PSI-7409, inhibited recombinant NS5B polymerases from genotypes 1 to 4 with comparable 50% inhibitory concentrations. PSI-7851 is a specific HCV inhibitor, as it lacks antiviral activity against other closely related and unrelated viruses. PSI-7409 also lacked any significant activity against cellular DNA and RNA polymerases. No cytotoxicity, mitochondrial toxicity, or bone marrow toxicity was associated with PSI-7851 at the highest concentration tested (100 μM). Crossresistance studies using replicon mutants conferring resistance to modified nucleoside analogs showed that PSI-7851 was less active against the S282T replicon mutant, whereas cells expressing a replicon containing the S96T/N142T mutation remained fully susceptible to PSI-7851. Clearance studies using replicon cells demonstrated that PSI-7851 was able to clear cells of HCV replicon RNA and prevent viral rebound.

UR - http://www.scopus.com/inward/record.url?scp=77954646871&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954646871&partnerID=8YFLogxK

U2 - 10.1128/AAC.00399-10

DO - 10.1128/AAC.00399-10

M3 - Article

VL - 54

SP - 3187

EP - 3196

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 8

ER -