Han Zhiqiang, Liang Xiao, Wang Yaxin, Qing Jie, Cao Lin, Shang Luqing, Yin Zheng
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, People's Republic of China.
Structural Biology Laboratory, Tsinghua University, Beijing 100084, People's Republic of China.
Eur J Med Chem. 2016 Jun 30;116:147-155. doi: 10.1016/j.ejmech.2016.03.062. Epub 2016 Mar 26.
In this study, a library of in-house small molecule was screened using a HCV cell-based assay and a compound (1) containing an N-protected indole scaffold (NINS) was identified as a novel anti-HCV inhibitor. Through structure activity relationship (SAR) study, it was observed that the racemic inhibitor (10m) displayed good anti-HCV activity (EC50 = 1.02 ± 0.10 μM) with the excellent selectivity index (SI = 45.56). Interestingly, R-enantiomer ((R)-10m) showed better anti-HCV activity and lower cytotoxicity than S-enantiomer ((S)-10m). (R)-10m gave the best anti-HCV potency (EC50 = 0.72 ± 0.09 μM) with the highest selectivity index (SI > 69.44). In addition, the mechanism of action study of NINS derivatives demonstrated that NINS derivatives interfere with the early step (viral entry) of the HCV life cycle.
在本研究中，使用基于丙型肝炎病毒（HCV）细胞的检测方法对一个内部小分子文库进行了筛选，一种含有N-保护吲哚支架（NINS）的化合物（1）被鉴定为新型抗HCV抑制剂。通过构效关系（SAR）研究发现，外消旋抑制剂（10m）显示出良好的抗HCV活性（半数有效浓度EC50 = 1.02±0.10 μM），且具有优异的选择性指数（SI = 45.56）。有趣的是，R-对映体（(R)-10m）比S-对映体（(S)-10m）表现出更好的抗HCV活性和更低的细胞毒性。(R)-10m具有最佳的抗HCV效力（EC50 = 0.72±0.09 μM）和最高的选择性指数（SI>69.44）。此外，对NINS衍生物的作用机制研究表明，NINS衍生物干扰了HCV生命周期的早期步骤（病毒进入）。
