Powers Jay P, Piper Derek E, Li Yang, Mayorga Veronica, Anzola John, Chen James M, Jaen Juan C, Lee Gary, Liu Jinqian, Peterson M Greg, Tonn George R, Ye Qiuping, Walker Nigel P C, Wang Zhulun
Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
J Med Chem. 2006 Feb 9;49(3):1034-46. doi: 10.1021/jm050859x.
Novel non-nucleoside inhibitors of the HCV RNA polymerase (NS5b) with sub-micromolar biochemical potency have been identified which are selective for the inhibition of HCV NS5b over other polymerases. The structures of the complexes formed between several of these inhibitors and HCV NS5b were determined by X-ray crystallography, and the inhibitors were found to bind in an allosteric binding site separate from the active site. Structure-activity relationships and structural studies have identified the mechanism of action for compounds in this series, several of which possess drug-like properties, as unique, reversible, covalent inhibitors of HCV NS5b.
已鉴定出对丙型肝炎病毒（HCV）RNA聚合酶（NS5b）具有亚微摩尔生化活性的新型非核苷抑制剂，这些抑制剂对HCV NS5b的抑制作用具有选择性，优于其他聚合酶。通过X射线晶体学确定了其中几种抑制剂与HCV NS5b形成的复合物的结构，发现这些抑制剂结合在一个与活性位点分开的变构结合位点。构效关系和结构研究确定了该系列化合物的作用机制，其中几种具有类药物特性，是HCV NS5b独特的、可逆的共价抑制剂。
