Lee Yu-Ming, Duh Yulander, Wang Shih-Ting, Lai Michael M C, Yuan Hanna S, Lim Carmay
Institute of Biomedical Sciences, Academia Sinica , Taipei 115, Taiwan.
Institute of Molecular Biology, Academia Sinica , Taipei 115, Taiwan.
J Am Chem Soc. 2016 Mar 23;138(11):3856-62. doi: 10.1021/jacs.6b00299. Epub 2016 Mar 14.
In viral proteins, labile Zn-sites, where Zn(2+) 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 Zn(2+) 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.
在病毒蛋白中，不稳定的锌位点是很有前景的药物靶点，在这些位点，锌离子（Zn(2+)）对于维持蛋白质天然结构至关重要，但与锌结合的半胱氨酸具有反应活性。在此，我们旨在：（i）利用我们之前工作建立的指导原则，识别病毒蛋白中的不稳定锌位点；（ii）评估临床安全的锌离子排出剂是否能从预测的靶点位点排出锌离子（Zn(2+)），从而抑制病毒复制。作为概念验证，我们在丙型肝炎病毒（HCV）NS5A蛋白中识别出一个不稳定锌位点，并表明戒酒药物双硫仑抑制HCV复制的程度与临床使用的抗病毒药物利巴韦林相似。发现一个新的病毒靶点以及双硫仑在抑制HCV复制中的新作用，将增强对抗HCV的治疗手段。所提出的策略也可用于识别其他细菌或病毒蛋白中的不稳定位点，这些位点可被双硫仑或其他临床安全的锌离子排出剂靶向。
