-transparent.png){kind=logo}
Novel nonnucleoside inhibitor of hepatitis C virus RNA-dependent RNA polymerase. 2004
Anita Y M Howe, and
Johnathan Bloom, and
Carl J Baldick, and
Christopher A Benetatos, and
Huiming Cheng, and
Joel S Christensen, and
Srinivas K Chunduru, and
Glen A Coburn, and
Boris Feld, and
Ariamala Gopalsamy, and
William P Gorczyca, and
Steve Herrmann, and
Stephen Johann, and
Xiaoqun Jiang, and
Michelle L Kimberland, and
Girija Krisnamurthy, and
Matthew Olson, and
Mark Orlowski, and
Steve Swanberg, and
Ian Thompson, and
Megan Thorn, and
Alfred Del Vecchio, and
Dorothy C Young, and
Marja van Zeijl, and
John W Ellingboe, and
Janis Upeslacis, and
Marc Collett, and
Tarek S Mansour, and
John F O'Connell
Infectious Diseases Wyeth Research, Pearl River, New York 10965, USA. howeaym@wyeth.com
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 microM 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.
Related Publications
Anita Y M Howe, and
Johnathan Bloom, and
Carl J Baldick, and
Christopher A Benetatos, and
Huiming Cheng, and
Joel S Christensen, and
Srinivas K Chunduru, and
Glen A Coburn, and
Boris Feld, and
Ariamala Gopalsamy, and
William P Gorczyca, and
Steve Herrmann, and
Stephen Johann, and
Xiaoqun Jiang, and
Michelle L Kimberland, and
Girija Krisnamurthy, and
Matthew Olson, and
Mark Orlowski, and
Steve Swanberg, and
Ian Thompson, and
Megan Thorn, and
Alfred Del Vecchio, and
Dorothy C Young, and
Marja van Zeijl, and
John W Ellingboe, and
Janis Upeslacis, and
Marc Collett, and
Tarek S Mansour, and
John F O'Connell
August 2012,
Antimicrobial agents and chemotherapy,
Anita Y M Howe, and
Johnathan Bloom, and
Carl J Baldick, and
Christopher A Benetatos, and
Huiming Cheng, and
Joel S Christensen, and
Srinivas K Chunduru, and
Glen A Coburn, and
Boris Feld, and
Ariamala Gopalsamy, and
William P Gorczyca, and
Steve Herrmann, and
Stephen Johann, and
Xiaoqun Jiang, and
Michelle L Kimberland, and
Girija Krisnamurthy, and
Matthew Olson, and
Mark Orlowski, and
Steve Swanberg, and
Ian Thompson, and
Megan Thorn, and
Alfred Del Vecchio, and
Dorothy C Young, and
Marja van Zeijl, and
John W Ellingboe, and
Janis Upeslacis, and
Marc Collett, and
Tarek S Mansour, and
John F O'Connell
December 2006,
Antimicrobial agents and chemotherapy,
Anita Y M Howe, and
Johnathan Bloom, and
Carl J Baldick, and
Christopher A Benetatos, and
Huiming Cheng, and
Joel S Christensen, and
Srinivas K Chunduru, and
Glen A Coburn, and
Boris Feld, and
Ariamala Gopalsamy, and
William P Gorczyca, and
Steve Herrmann, and
Stephen Johann, and
Xiaoqun Jiang, and
Michelle L Kimberland, and
Girija Krisnamurthy, and
Matthew Olson, and
Mark Orlowski, and
Steve Swanberg, and
Ian Thompson, and
Megan Thorn, and
Alfred Del Vecchio, and
Dorothy C Young, and
Marja van Zeijl, and
John W Ellingboe, and
Janis Upeslacis, and
Marc Collett, and
Tarek S Mansour, and
John F O'Connell
February 2008,
Antimicrobial agents and chemotherapy,
Anita Y M Howe, and
Johnathan Bloom, and
Carl J Baldick, and
Christopher A Benetatos, and
Huiming Cheng, and
Joel S Christensen, and
Srinivas K Chunduru, and
Glen A Coburn, and
Boris Feld, and
Ariamala Gopalsamy, and
William P Gorczyca, and
Steve Herrmann, and
Stephen Johann, and
Xiaoqun Jiang, and
Michelle L Kimberland, and
Girija Krisnamurthy, and
Matthew Olson, and
Mark Orlowski, and
Steve Swanberg, and
Ian Thompson, and
Megan Thorn, and
Alfred Del Vecchio, and
Dorothy C Young, and
Marja van Zeijl, and
John W Ellingboe, and
Janis Upeslacis, and
Marc Collett, and
Tarek S Mansour, and
John F O'Connell
June 2009,
Antimicrobial agents and chemotherapy,
Anita Y M Howe, and
Johnathan Bloom, and
Carl J Baldick, and
Christopher A Benetatos, and
Huiming Cheng, and
Joel S Christensen, and
Srinivas K Chunduru, and
Glen A Coburn, and
Boris Feld, and
Ariamala Gopalsamy, and
William P Gorczyca, and
Steve Herrmann, and
Stephen Johann, and
Xiaoqun Jiang, and
Michelle L Kimberland, and
Girija Krisnamurthy, and
Matthew Olson, and
Mark Orlowski, and
Steve Swanberg, and
Ian Thompson, and
Megan Thorn, and
Alfred Del Vecchio, and
Dorothy C Young, and
Marja van Zeijl, and
John W Ellingboe, and
Janis Upeslacis, and
Marc Collett, and
Tarek S Mansour, and
John F O'Connell
July 2007,
Antimicrobial agents and chemotherapy,
Anita Y M Howe, and
Johnathan Bloom, and
Carl J Baldick, and
Christopher A Benetatos, and
Huiming Cheng, and
Joel S Christensen, and
Srinivas K Chunduru, and
Glen A Coburn, and
Boris Feld, and
Ariamala Gopalsamy, and
William P Gorczyca, and
Steve Herrmann, and
Stephen Johann, and
Xiaoqun Jiang, and
Michelle L Kimberland, and
Girija Krisnamurthy, and
Matthew Olson, and
Mark Orlowski, and
Steve Swanberg, and
Ian Thompson, and
Megan Thorn, and
Alfred Del Vecchio, and
Dorothy C Young, and
Marja van Zeijl, and
John W Ellingboe, and
Janis Upeslacis, and
Marc Collett, and
Tarek S Mansour, and
John F O'Connell
January 2000,
Current topics in microbiology and immunology,
Anita Y M Howe, and
Johnathan Bloom, and
Carl J Baldick, and
Christopher A Benetatos, and
Huiming Cheng, and
Joel S Christensen, and
Srinivas K Chunduru, and
Glen A Coburn, and
Boris Feld, and
Ariamala Gopalsamy, and
William P Gorczyca, and
Steve Herrmann, and
Stephen Johann, and
Xiaoqun Jiang, and
Michelle L Kimberland, and
Girija Krisnamurthy, and
Matthew Olson, and
Mark Orlowski, and
Steve Swanberg, and
Ian Thompson, and
Megan Thorn, and
Alfred Del Vecchio, and
Dorothy C Young, and
Marja van Zeijl, and
John W Ellingboe, and
Janis Upeslacis, and
Marc Collett, and
Tarek S Mansour, and
John F O'Connell
January 1999,
Methods in molecular medicine,
Anita Y M Howe, and
Johnathan Bloom, and
Carl J Baldick, and
Christopher A Benetatos, and
Huiming Cheng, and
Joel S Christensen, and
Srinivas K Chunduru, and
Glen A Coburn, and
Boris Feld, and
Ariamala Gopalsamy, and
William P Gorczyca, and
Steve Herrmann, and
Stephen Johann, and
Xiaoqun Jiang, and
Michelle L Kimberland, and
Girija Krisnamurthy, and
Matthew Olson, and
Mark Orlowski, and
Steve Swanberg, and
Ian Thompson, and
Megan Thorn, and
Alfred Del Vecchio, and
Dorothy C Young, and
Marja van Zeijl, and
John W Ellingboe, and
Janis Upeslacis, and
Marc Collett, and
Tarek S Mansour, and
John F O'Connell
January 1996,
Methods in enzymology,
Anita Y M Howe, and
Johnathan Bloom, and
Carl J Baldick, and
Christopher A Benetatos, and
Huiming Cheng, and
Joel S Christensen, and
Srinivas K Chunduru, and
Glen A Coburn, and
Boris Feld, and
Ariamala Gopalsamy, and
William P Gorczyca, and
Steve Herrmann, and
Stephen Johann, and
Xiaoqun Jiang, and
Michelle L Kimberland, and
Girija Krisnamurthy, and
Matthew Olson, and
Mark Orlowski, and
Steve Swanberg, and
Ian Thompson, and
Megan Thorn, and
Alfred Del Vecchio, and
Dorothy C Young, and
Marja van Zeijl, and
John W Ellingboe, and
Janis Upeslacis, and
Marc Collett, and
Tarek S Mansour, and
John F O'Connell
November 2003,
Antimicrobial agents and chemotherapy,
Anita Y M Howe, and
Johnathan Bloom, and
Carl J Baldick, and
Christopher A Benetatos, and
Huiming Cheng, and
Joel S Christensen, and
Srinivas K Chunduru, and
Glen A Coburn, and
Boris Feld, and
Ariamala Gopalsamy, and
William P Gorczyca, and
Steve Herrmann, and
Stephen Johann, and
Xiaoqun Jiang, and
Michelle L Kimberland, and
Girija Krisnamurthy, and
Matthew Olson, and
Mark Orlowski, and
Steve Swanberg, and
Ian Thompson, and
Megan Thorn, and
Alfred Del Vecchio, and
Dorothy C Young, and
Marja van Zeijl, and
John W Ellingboe, and
Janis Upeslacis, and
Marc Collett, and
Tarek S Mansour, and
John F O'Connell
September 2011,
Antimicrobial agents and chemotherapy,
