Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model

Chin Ming Chen, Yupeng He, Liangjun Lu, Hock Ben Lim, Rakesh L. Tripathi, Tim Middleton, Lisa E. Hernandez, David W A Beno, Michelle A. Long, Warren M. Kati, Todd D. Bosse, Daniel P. Larson, Rolf Wagner, Robert E. Lanford, William E. Kohlbrenner, Dale J. Kempf, Tami J. Pilot-Matias, Akhteruzzaman Molla

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

A-837093 is a potent and specific nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase. It possesses nanomolar potencies in both enzymatic and replicon-based cell culture assays. In rats and dogs this compound demonstrated an oral plasma half-life of greater than 7 h, and its bioavailability was >60%. In monkeys it had a half-life of 1.9 h and 15% bioavailability. Its antiviral efficacy was evaluated in two chimpanzees infected with HCV in a proof-of-concept study. The design included oral dosing of 30 mg per kg of body weight twice a day for 14 days, followed by a 14-day posttreatment observation. Maximum viral load reductions of 1.4 and 2.5 log10 copies RNA/ml for genotype 1a-and 1b-infected chimpanzees, respectively, were observed within 2 days after the initiation of treatment. After this initial drop in the viral load, a rebound of plasma HCV RNA was observed in the genotype 1b-infected chimpanzee, while the genotype 1a-infected chimpanzee experienced a partial rebound that lasted throughout the treatment period. Clonal analysis of NS5B gene sequences derived from the plasma of A-837093-treated chimpanzees revealed the presence of several mutations associated with resistance to A-837093, including Y448H, G554D, and D559G in the genotype 1a-infected chimpanzee and C316Y and G554D in the genotype 1b-infected chimpanzee. The identification of resistance-associated mutations in both chimpanzees is consistent with the findings of in vitro selection studies, in which many of the same mutations were selected. These findings validate the antiviral efficacy and resistance development of benzothiadiazine HCV polymerase inhibitors in vivo.

Original languageEnglish (US)
Pages (from-to)4290-4296
Number of pages7
JournalAntimicrobial Agents and Chemotherapy
Volume51
Issue number12
DOIs
StatePublished - Dec 2007
Externally publishedYes

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Pan troglodytes
Hepacivirus
Genotype
Viral Load
Mutation
Biological Availability
Antiviral Agents
Half-Life
Benzothiadiazines
RNA
RNA Replicase
Replicon
Haplorhini
Proteins
Cell Culture Techniques
Body Weight
Observation
Dogs

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Chen, C. M., He, Y., Lu, L., Lim, H. B., Tripathi, R. L., Middleton, T., ... Molla, A. (2007). Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model. Antimicrobial Agents and Chemotherapy, 51(12), 4290-4296. https://doi.org/10.1128/AAC.00723-07

Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model. / Chen, Chin Ming; He, Yupeng; Lu, Liangjun; Lim, Hock Ben; Tripathi, Rakesh L.; Middleton, Tim; Hernandez, Lisa E.; Beno, David W A; Long, Michelle A.; Kati, Warren M.; Bosse, Todd D.; Larson, Daniel P.; Wagner, Rolf; Lanford, Robert E.; Kohlbrenner, William E.; Kempf, Dale J.; Pilot-Matias, Tami J.; Molla, Akhteruzzaman.

In: Antimicrobial Agents and Chemotherapy, Vol. 51, No. 12, 12.2007, p. 4290-4296.

Research output: Contribution to journalArticle

Chen, CM, He, Y, Lu, L, Lim, HB, Tripathi, RL, Middleton, T, Hernandez, LE, Beno, DWA, Long, MA, Kati, WM, Bosse, TD, Larson, DP, Wagner, R, Lanford, RE, Kohlbrenner, WE, Kempf, DJ, Pilot-Matias, TJ & Molla, A 2007, 'Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model', Antimicrobial Agents and Chemotherapy, vol. 51, no. 12, pp. 4290-4296. https://doi.org/10.1128/AAC.00723-07
Chen, Chin Ming ; He, Yupeng ; Lu, Liangjun ; Lim, Hock Ben ; Tripathi, Rakesh L. ; Middleton, Tim ; Hernandez, Lisa E. ; Beno, David W A ; Long, Michelle A. ; Kati, Warren M. ; Bosse, Todd D. ; Larson, Daniel P. ; Wagner, Rolf ; Lanford, Robert E. ; Kohlbrenner, William E. ; Kempf, Dale J. ; Pilot-Matias, Tami J. ; Molla, Akhteruzzaman. / Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model. In: Antimicrobial Agents and Chemotherapy. 2007 ; Vol. 51, No. 12. pp. 4290-4296.
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