Novel inhibitors of hepatitis C virus RNA-dependent RNA polymerases.
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 0.54muM and 0.44muM, 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.
Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, USA.
Gary
G
Lee
Derek E
DE
Piper
Zhulun
Z
Wang
John
J
Anzola
Jay
J
Powers
Nigel
N
Walker
Yang
Y
Li
D016174:Hepacivirus / Q000201:enzymology* / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D017434:Protein Structure, Tertiary; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D013844:Thiazoles; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase