NS5B Polymerase Non-Nucleoside Inhibitors
Martijn Fenaux and Hongmei Mo
from: Hepatitis C: Antiviral Drug Discovery and Development (Edited by: Seng-Lai Tan and Yupeng He). Caister Academic Press, U.K. (2011)
Abstract
The inhibitors of HCV NS5B polymerase consist of 2 classes: nucleoside inhibitors and non-nucleoside inhibitors. In contrast to the nucleoside inhibitors which bind to the active Site of the polymerase, the HCV non-nucleoside polymerase inhibitors binds to one of the four allosteric binding Sites within the NS5B polymerase including: Site 1 (Thumb I) for JTK-109, Site II (Thumb II) for PF-868554, VCH-759, VCH-916 and VCH-222, Site III (Palm I) for ANA-598, A-848837 and ABT-333, and Site IV (Palm II) for HCV-796. Among these non-nucleoside inhibitors, HCV-796 was the first inhibitor to show an antiviral effect in HCV-infected patients. However, the development of this compound was discontinued due to the hepatic toxicity. Subsequently, PF-868554, VCH-759, VCH-916, VCH-222, ANA-598, and ABT-333 demonstrated antiviral activity in early clinical trials and some have been advanced to phase II. Due to their distinctive binding sites, non-nucleoside polymerase inhibitors selected different NS5B mutations which exhibited non-cross-resistance profiles. Therefore, combination of non-nucleoside inhibitors may reduce the development of resistance. Given the importance of the NS5B non-nucleoside polymerase inhibitors for the treatment of HCV, this chapter will describes the preclinical resistance profiles as well as the clinical results of the above inhibitors read more ...
