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Antimicrobial Agents and Chemotherapy, December 2004, p. 4813-4821, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4813-4821.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Novel Nonnucleoside Inhibitor of Hepatitis C Virus RNA-Dependent RNA Polymerase

Anita Y. M. Howe,1* Johnathan Bloom,2 Carl J. Baldick,1,{dagger} Christopher A. Benetatos,3 Huiming Cheng,1 Joel S. Christensen,3 Srinivas K. Chunduru,3 Glen A. Coburn,3 Boris Feld,1 Ariamala Gopalsamy,2 William P. Gorczyca,3,{ddagger} Steve Herrmann,1 Stephen Johann,1 Xiaoqun Jiang,1 Michelle L. Kimberland,3 Girija Krisnamurthy,2 Matthew Olson,1 Mark Orlowski,1 Steve Swanberg,1 Ian Thompson,1 Megan Thorn,1 Alfred Del Vecchio,3,§ Dorothy C. Young,3 Marja van Zeijl,1 John W. Ellingboe,2 Janis Upeslacis,2 Marc Collett,3 Tarek S. Mansour,2 and John F. O'Connell1

Infectious Diseases,1 Chemical and Screening Sciences, Wyeth Research, Pearl River, New York,2 ViroPharma Incorporated, Exton, Pennsylvania3

Received 7 May 2004/ Returned for modification 1 July 2004/ Accepted 17 August 2004

A novel nonnucleoside inhibitor of hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp), [(1R)-5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyano[3,4-b]indol-1-yl] acetic acid (HCV-371), was discovered through high-throughput screening followed by chemical optimization. HCV-371 displayed broad inhibitory activities against the NS5B RdRp enzyme, with 50% inhibitory concentrations ranging from 0.3 to 1.8 µM for 90% of the isolates derived from HCV genotypes 1a, 1b, and 3a. HCV-371 showed no inhibitory activity against a panel of human polymerases, including mitochondrial DNA polymerase gamma, and other unrelated viral polymerases, demonstrating its specificity for the HCV polymerase. A single administration of HCV-371 to cells containing the HCV subgenomic replicon for 3 days resulted in a dose-dependent reduction of the steady-state levels of viral RNA and protein. Multiple treatments with HCV-371 for 16 days led to a >3-log10 reduction in the HCV RNA level. In comparison, multiple treatments with a similar inhibitory dose of alpha interferon resulted in a 2-log10 reduction of the viral RNA level. In addition, treatment of cells with a combination of HCV-371 and pegylated alpha interferon resulted in an additive antiviral activity. Within the effective antiviral concentrations of HCV-371, there was no effect on cell viability and metabolism. The intracellular antiviral specificity of HCV-371 was demonstrated by its lack of activity in cells infected with several DNA or RNA viruses. Fluorescence binding studies show that HCV-371 binds the NS5B with an apparent dissociation constant of 150 nM, leading to high selectivity and lack of cytotoxicity in the antiviral assays.

* Corresponding author. Mailing address: Wyeth Research, 410 N. Middletown Rd., Pearl River, NY 10965. Phone: (845) 602-3596. Fax: (845) 602-4941. E-mail: howeaym{at}wyeth.com.

{dagger} Present address: Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT 06492.

{ddagger} Present address: Pfizer Central Research Division, Groton, CT 06340.

§ Present address: Centocor, Inc., Radnor, PA 19087.

Antimicrobial Agents and Chemotherapy, December 2004, p. 4813-4821, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4813-4821.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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