Discovery of Hepatitis C Virus NS3-NS4A Complex Inhibitors
Mingjun Huang, Kathe Stauber, Atul Agarwal, Milind Deshpande and Avinash Phadke
from: Hepatitis C: Antiviral Drug Discovery and Development (Edited by: Seng-Lai Tan and Yupeng He). Caister Academic Press, U.K. (2011)
Hepatitis C virus (HCV) infection is a serious global health problem because of its high prevalence, chronic nature and significant morbidity of the resulting diseases. The current standard of care (peginterferon α-2a/b and ribavirin combination) is limited by numerous side-effects and suboptimal efficacy in genotype-1 HCV-infected patients underscoring the unmet medical need for new therapies. Here we describe our efforts in discovery and optimization of a novel series of specific inhibitors leading to the nomination of ACH-806 (or GS-9132) for clinical development. These inhibitors interrupt the functions of HCV NS3-NS4A complex likely by binding to NS4A. We have summarized our studies on antiviral activity, resistance induction, mechanism of action, and pharmacokinetics with selected inhibitors including ACH-806. Finally, we present the data on a proof-of concept clinical trial with ACH-806 that validates this novel mechanism of action read more ...