Novel Inhibitors of Hepatitis C Virus RNA-dependent RNA Polymerases

• Published in: Journal of molecular biology 2006-04, Vol.357 (4), p.1051-1057
• Main Authors: Lee, Gary, Piper, Derek E., Wang, Zhulun, Anzola, John, Powers, Jay, Walker, Nigel, Li, Yang
• Format: Article
• Language: English
• Subjects: HCV; Hepacivirus - enzymology; Hepacivirus - genetics; Hepatitis C - drug therapy; Hepatitis C virus; Humans; inhibitor; Models, Molecular; Molecular Structure; NS5B; Protein Structure, Tertiary; RNA-dependent RNA polymerase; RNA-Dependent RNA Polymerase - antagonists & inhibitors; RNA-Dependent RNA Polymerase - metabolism; structure; Thiazoles - chemistry; Thiazoles - metabolism; Thiazoles - therapeutic use; Viral Nonstructural Proteins - chemistry; Viral Nonstructural Proteins - genetics; Viral Nonstructural Proteins - metabolism
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2006.01.032

Hepatitis C virus (HCV) is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma worldwide-and is the main cause of adult liver transplants in developed nations. We have identified a class of novel and specific inhibitors of HCV NS5B RNA-dependent RNA polymerase (RdRp) activity in vitro. Characterization of two such inhibitors, COMPOUND1 (5-(4-chlorophenylmethylene)-3-(benzenesulfonylamino)-4-oxxo-2-thionothiazolidine) and COMPOUND2 (5-(4-bromophenylmethylene)-3-(benzenesulfonylamino)-4-oxxo-2-thionothiazolidine), is reported here. With IC 50 values of 0.54 μM and 0.44 μM, respectively, they are reversible and non-competitive with nucleotides. Biochemical and structural studies have suggested that these compounds can inhibit the initiation of the RdRp reaction. Interestingly, these inhibitors appear to form a reversible covalent bond with the NS5B cysteine 366, a residue that is not only conserved among all HCV genotypes and a large family of viruses but also required for full NS5B RdRp activity. This may reduce the potential resistance of the viruses to this class of inhibitors.