Heteroaromatic ester inhibitors of hepatitis A virus 3C proteinase: Evaluation of mode of action

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• 作者：Carly Huitema ; Jianmin Zhang ; Jiang Yin ; Michael N.G. James ; John C. Vederas ; Lindsay D. Eltis
• 关键词：Cysteine proteinase ; Antiviral ; Picornavirus ; Halopyridinyl ester
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2008
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：15 May 2008
• 卷：16
• 期：10
• 页码：5761-5777
• 文件大小：978 K

摘要

The related 3C and 3C-like proteinase (3C^pro and 3CL^pro) of picornaviruses and coronaviruses, respectively, are good drug targets. As part of an effort to generate broad-spectrum inhibitors of these enzymes, we screened a library of inhibitors based on a halopyridinyl ester from a previous study of the severe acute respiratory syndrome (SARS) 3CL proteinase against Hepatitis A virus (HAV) 3C^pro. Three of the compounds, which also had furan rings, inhibited the cleavage activity of HAV 3C^pro with K_ics of 120–240 nM. HPLC-based assays revealed that the inhibitors were slowly hydrolyzed by both HAV 3C^pro and SARS 3CL^pro, confirming the identity of the expected products. Mass spectrometric analyses indicated that this hydrolysis proceeded via an acyl-enzyme intermediate. Modeling studies indicated that the halopyridinyl moiety of the inhibitor fits tightly into the S1-binding pocket, consistent with the lack of tolerance of the inhibitors to modification in this portion of the molecule. These compounds are among the most potent non-peptidic inhibitors reported to date against a 3C^pro.