Amblard Franck, Zhou Shaoman, Liu Peng, Yoon Jack, Cox Bryan, Muzzarelli Kendall, Kuiper Benjamin D, Kovari Ladislau C, Schinazi Raymond F
Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Bioorg Med Chem Lett. 2018 Jul 1;28(12):2165-2170. doi: 10.1016/j.bmcl.2018.05.012. Epub 2018 May 8.
A series of tripeptidyl transition state inhibitors with new P1 and warhead moieties were synthesized and evaluated in a GI-1 norovirus replicon system and against GII-4 and GI-1 norovirus proteases. Compound 19, containing a 6-membered ring at the P1 position and a reactive aldehyde warhead exhibited sub-micromolar replicon inhibition. Retaining the same peptidyl scaffold, several reactive warheads were tested for protease inhibition and norovirus replicon inhibition. Of the six that were synthesized and tested, compounds 42, 43, and 45 potently inhibited the protease in biochemical assay and GI-1 norovirus replicon in the nanomolar range.
合成了一系列具有新的P1和弹头部分的三肽基过渡态抑制剂，并在GI-1诺如病毒复制子系统中以及针对GII-4和GI-1诺如病毒蛋白酶进行了评估。化合物19在P1位置含有一个六元环和一个反应性醛弹头，表现出亚微摩尔级的复制子抑制作用。保留相同的肽基支架，测试了几种反应性弹头对蛋白酶的抑制作用和对诺如病毒复制子的抑制作用。在合成并测试的六种化合物中，化合物42、43和45在生化测定中能有效抑制蛋白酶，在纳摩尔范围内抑制GI-1诺如病毒复制子。
