Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, Newark, NJ 07103, USA.
Eur J Med Chem. 2012 Mar;49:191-9. doi: 10.1016/j.ejmech.2012.01.010. Epub 2012 Jan 12.
Structure-based studies led to the identification of a constrained derivative of S-trityl-l-cysteine (STLC) scaffold as a candidate inhibitor of hepatitis C virus (HCV) NS5B polymerase. A panel of STLC derivatives were synthesized and investigated for their activity against HCV NS5B. Three STLC derivatives, 9, F-3070, and F-3065, were identified as modest HCV NS5B inhibitors with IC(50) values between 22.3 and 39.7 μM. F-3070 and F-3065 displayed potent inhibition of intracellular NS5B activity in the BHK-NS5B-FRLuc reporter and also inhibited HCV RNA replication in the Huh7/Rep-Feo1b reporter system. Binding mode investigations suggested that the STLC scaffold can be used to develop new NS5B inhibitors by further chemical modification at one of the trityl phenyl group.
基于结构的研究导致了 S-三苯甲基-L-半胱氨酸（STLC）支架的约束衍生物的鉴定，作为候选的丙型肝炎病毒（HCV）NS5B 聚合酶抑制剂。合成了一组 STLC 衍生物，并研究了它们对 HCV NS5B 的活性。鉴定出三种 STLC 衍生物，9、F-3070 和 F-3065，它们是适度的 HCV NS5B 抑制剂，IC（50）值在 22.3 和 39.7 μM 之间。F-3070 和 F-3065 在 BHK-NS5B-FRLuc 报告子中显示出对细胞内 NS5B 活性的有效抑制作用，并且在 Huh7/Rep-Feo1b 报告子系统中也抑制 HCV RNA 复制。结合模式研究表明，通过进一步在三苯甲基苯基之一进行化学修饰，可以利用 STLC 支架来开发新的 NS5B 抑制剂。
