Hepatitis C virus NS3 serine protease as a drug discovery target

Abstract

Hepatitis C virus NS3 serine protease (HCV-Pr) is an extensively studied enzyme for drug intervention. The target presented serious challenges in early screening efforts, however, wish the lack of prominent active site features rendering traditional nonpeptidic serine protease inhibitor motifs and high-throughput screening campaigns ineffectual. In contrast, the peptidomimetic structure-based design approach has proven uccessful in the discovery of potent inhibitors of HCV Pr. Subsequent rational design efforts have led to the identification of an inhibitor that demonstrates efficacy in man, validating the years of research. This review summarizes why HCV Pr provides a viable drug discovery target despite the many obstacies, and details the breakthroughs in protein production and essay development that have facilitated inhibitor advances. The latest inhibitors in preclinical and clinical research and development are also presented, along with a discussion of how the recent HCV Pr clinical candidate chalienges much of the dogma surrounding peptidomimetic design. In addition, future issues such as resistance, genotype coverage and HIV-HCV coinfected individuals are considered.