Isothiazoles as active-site inhibitors of HCVNS5B polymerase

被引：52

作者：

Yan, Shunqi ^{[1
]}

Appleby, Todd ^{[1
]}

Gunic, Esmir ^{[1
]}

Shim, Jae Hoon ^{[1
]}

Tasu, Tania ^{[1
]}

Kim, Hongwoo ^{[1
]}

Rong, Frank ^{[1
]}

Chen, Huaming ^{[1
]}

Hamatake, Robert ^{[1
]}

Wu, Jim Z. ^{[1
]}

Hong, Zhi ^{[1
]}

Yao, Nanhua ^{[1
]}

机构：

[1] Valean Pharmaceut Res & Dev, Costa Mesa, CA 92626 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 01期

关键词：

HCV; NS5B; NS5B inhibitor; HCVNS5B polymerase; HCVNS5B inhibitors; isothiazole; NS5B active-site inhibitor; covalent inhibitor;

D O I：

10.1016/j.bmcl.2006.10.002

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Isothiazole analogs were discovered as a novel class of active-site inhibitors of HCV NS5B polyrnerase. The best compound has an IC50 of 200 nM and EC50 of 100 nM, which is a significant improvement over the starting inhibitor (1). The X-ray complex structure of I with HCV NS5B was obtained at a resolution of 2.2 angstrom, revealing that the inhibitor is covalently linked with Cys 366 of the 'primer-grip'. Furthermore, it makes considerable contacts with the C-terminus, P-loop, and more importantly, to the active-site of the enzyme. The uniqueness of this binding mode offers a new insight for the rational design of novel inhibitors for HCV NS5B polymerase. (c) 2006 Elsevier Ltd. All rights reserved.

引用

页码：28 / 33

页数：6

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