Using an Old Drug to Target a New Drug Site: Application of Disulfiram to Target the Zn-Site in HCV NS5A Protein

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• 作者：Yu-Ming Lee ; Yulander Duh ; Shih-Ting Wang ; Michael M.C. Lai ; Hanna S. Yuan ; Carmay Lim
• 刊名：Journal of the American Chemical Society
• 出版年：2016
• 出版时间：March 23, 2016
• 年：2016
• 卷：138
• 期：11
• 页码：3856-3862
• 全文大小：413K
• ISSN：1520-5126

文摘

In viral proteins, labile Zn-sites, where Zn²⁺ is crucial for maintaining the native protein structure but the Zn-bound cysteines are reactive, are promising drug targets. Here, we aim to (i) identify labile Zn-sites in viral proteins using guidelines established from our previous work and (ii) assess if clinically safe Zn-ejecting agents could eject Zn²⁺ from the predicted target site and thus inhibit viral replication. As proof-of-concept, we identified a labile Zn-site in the hepatitis C virus (HCV) NS5A protein and showed that the antialcoholism drug, disulfiram, could inhibit HCV replication to a similar extent as the clinically used antiviral agent, ribavirin. The discovery of a novel viral target and a new role for disulfiram in inhibiting HCV replication will enhance the therapeutic armamentarium against HCV. The strategy presented can also be applied to identify labile sites in other bacterial or viral proteins that can be targeted by disulfiram or other clinically safe Zn-ejectors.