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Isothiazoles as active-site inhibitors of HCV NS5B polymerase. 2007
Shunqi Yan, and
Todd Appleby, and
Esmir Gunic, and
Jae Hoon Shim, and
Tania Tasu, and
Hongwoo Kim, and
Frank Rong, and
Huaming Chen, and
Robert Hamatake, and
Jim Z Wu, and
Zhi Hong, and
Nanhua Yao
Valeant Pharmaceutical Research and Development, 3300 Hyland Ave., Costa Mesa, CA 92626, USA. syan@valeant.com
Isothiazole analogs were discovered as a novel class of active-site inhibitors of HCV NS5B polymerase. The best compound has an IC(50) of 200 nM and EC(50) of 100 nM, which is a significant improvement over the starting inhibitor (1). The X-ray complex structure of 1 with HCV NS5B was obtained at a resolution of 2.2A, revealing that the inhibitor is covalently linked with Cys 366 of the 'primer-grip'. Furthermore, it makes considerable contacts with the C-terminus, beta-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.
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