Synthesis and invitro Evaluation of West Nile Virus Protease Inhibitors Based on the 2-{6-[2-(5-Phenyl-4H-{1,2,4]triazol-3-ylsulfanyl)acetylamino]benzothiazol-2-ylsulfanyl}acetamide Scaffold
Synthesis and invitro Evaluation of West Nile Virus Protease Inhibitors Based on the 2-{6-[2-(5-Phenyl-4H-{1,2,4]triazol-3-ylsulfanyl)acetylamino]benzothiazol-2-ylsulfanyl}acetamide Scaffold
复制标题
DOI：
10.1002/cmdc.201300114
复制
发表时间：
2013-06-01
期刊：
影响因子：
3.4
通讯作者：
Lam, Yulin
中科院分区：
文献类型：
--
作者：
Samanta, Sanjay;Lim, Ting Liang;Lam, Yulin
近年来，西尼罗河病毒（WNV）感染引起的临床症状日益严重，老年人中神经侵袭性疾病的发病率也随之增加。由于目前尚无成功的针对人类西尼罗河病毒的疗法，因此非常需要不断努力开发针对该病毒的新化疗药物。病毒 NS2B-NS3 蛋白酶因其在病毒复制中的重要性及其独特的底物偏好而成为病毒抑制的有前途的靶标。在这项研究中，在筛选过程中鉴定出了一种具有 2-{6-[2-(5-苯基-4H-[1,2,4]三唑-3-基硫基)乙酰氨基]苯并噻唑-2-基硫基}乙酰胺支架的 WNV NS2B-NS3 蛋白酶抑制剂。通过使用该支架合成和筛选重点化合物库来优化该初始命中，从而鉴定出 WNV NS2B-NS3 蛋白酶的新型非竞争性抑制剂（1a24，IC50=3.4 +/- 0.2M）。 1a24 与 WNV 蛋白酶的分子对接表明，该化合物干扰 NS2B 辅因子与 NS3 蛋白酶的有效相互作用，并且是 WNV NS3 蛋白酶的变构抑制剂。
In recent years, clinical symptoms resulting from West Nile virus (WNV) infection have worsened in severity, with an increased frequency in neuroinvasive diseases among the elderly. As there are presently no successful therapies against WNV for use in humans, continual efforts to develop new chemotherapeutics against this virus are highly desired. The viral NS2B-NS3 protease is a promising target for viral inhibition due to its importance in viral replication and its unique substrate preference. In this study, a WNV NS2B-NS3 protease inhibitor with a 2-{6-[2-(5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)acetylamino]benzothiazol-2-ylsulfanyl}acetamide scaffold was identified during screening. Optimization of this initial hit by synthesis and screening of a focused compound library with this scaffold led to the identification of a novel uncompetitive inhibitor (1a24, IC50=3.4 +/- 0.2M) of the WNV NS2B-NS3 protease. Molecular docking of 1a24 into the WNV protease showed that the compound interferes with productive interactions of the NS2B cofactor with the NS3 protease and is an allosteric inhibitor of the WNV NS3 protease.