Abstract
X-ray crystal structures of two non-nucleoside analogue inhibitors bound to hepatitis C virus NS5B RNA-dependent RNA polymerase have been determined to 2.0 and 2.9 A resolution. These noncompetitive inhibitors bind to the same site on the protein, approximately 35 A from the active site. The common features of binding include a large hydrophobic region and two hydrogen bonds between both oxygen atoms of a carboxylate group on the inhibitor and two main chain amide nitrogen atoms of Ser(476) and Tyr(477) on NS5B. The inhibitor-binding site lies at the base of the thumb domain, near its interface with the C-terminal extension of NS5B. The location of this inhibitor-binding site suggests that the binding of these inhibitors interferes with a conformational change essential for the activity of the polymerase.
Highlights
X-ray crystal structures of two non-nucleoside analogue inhibitors bound to hepatitis C virus NS5B RNAdependent RNA polymerase have been determined to 2.0 and 2.9 Å resolution
Hepatitis C virus (HCV) infection can develop into chronic hepatitis, which, in some cases, causes cirrhosis of the liver, eventually leading to hepatocellular carcinoma [1]
In the case of HCV NS5B polymerase, both nucleoside and non-nucleoside inhibitors have been discovered in recent years [16]. 3TC (2Ј-deoxy-3Ј-thiacytidine proprietary compound lamivudine) triphosphate has been reported to have a weak inhibitory effect with a 50% inhibitory concentration (IC50) of 180 M [17], whereas numerous non-nucleoside compounds have been documented to possess relatively potent antiNS5B activity
Summary
X-ray crystal structures of two non-nucleoside analogue inhibitors bound to hepatitis C virus NS5B RNAdependent RNA polymerase have been determined to 2.0 and 2.9 Å resolution These noncompetitive inhibitors bind to the same site on the protein, ϳ35 Å from the active site. We present the three-dimensional structures of two HCV NS5B polymerase/inhibitor complexes These inhibitors were synthesized as part of structure-activity relationship optimization (SAR) program and are phenylalanine derivatives compound A ((2s)-2-[(2,4-dichloro-benzoyl)-(3-trifluoromethylbenzyl)-amino]-3-phenyl-propionic acid) and compound B ((2s)2-[(5-Benzofuran-2-yl-thiophen-2-ylmethyl)-(2,4-dichlorobenzoyl)-amino]-3-phenyl-propionic acid) (see Fig. 1a).. These inhibitors were synthesized as part of structure-activity relationship optimization (SAR) program and are phenylalanine derivatives compound A ((2s)-2-[(2,4-dichloro-benzoyl)-(3-trifluoromethylbenzyl)-amino]-3-phenyl-propionic acid) and compound B ((2s)2-[(5-Benzofuran-2-yl-thiophen-2-ylmethyl)-(2,4-dichlorobenzoyl)-amino]-3-phenyl-propionic acid) (see Fig. 1a).2 Both occupy a common binding site in the thumb subdomain near to the C terminus of NS5B polymerase. The detailed interactions between NS5B and inhibitors, revealed by crystallographic
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