Design of Selective Eglin Inhibitors of HCV NS3 Proteinase

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• 作者：Franck Martin ; Nazzareno Dimasi ; Cinzia Volpari ; Claudia Perrera ; Stefania Di Marco ; Mirko Brunetti ; Christian Steinkü ; hler ; Raffaele De Francesco ; and Maurizio Sollazzo
• 刊名：Biochemistry
• 出版年：1998
• 出版时间：August 18, 1998
• 年：1998
• 卷：37
• 期：33
• 页码：11459 - 11468
• 全文大小：214K
• 年卷期：v.37,no.33(August 18, 1998)
• ISSN：1520-4995

文摘

Hepatitis C virus (HCV) infection is a major health problem that leads to cirrhosis andhepatocellular carcinoma in a substantial number of infected individuals, estimated to be 100-200 millionworldwide. Unfortunately, immunotherapy or other effective treatments for HCV infection are not yetavailable, and interferon administration has limited efficacy. Different approaches to HCV therapy arebeing explored, and these include inhibition of the viral proteinase, helicase, and RNA-dependent RNApolymerase and development of a vaccine. Here we present the design of selective inhibitors withnanomolar potencies of HCV NS3 proteinase based on eglin c. These eglin c mutants were generated byreshaping the inhibitor active site-binding loop, and the results emphasize the role played by residuesP5-P4' in enzyme recognition. In addition, alanine scanning experiments provide evidence that the Nterminus of eglin c also contributes to NS3 binding. These eglin inhibitors offer a unique tool for accuratelyassessing the requirements for effective inhibition of the enzymatic activity of NS3 and at the same timecan be considered lead compounds for the identification of other NS3 inhibitors in targeted design efforts.