Laboratory of Virology and Chemotherapy, KU Leuven-Department of Microbiology, Immunology and Transplantation, Rega Institute, 3000 Leuven, Belgium.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
Viruses. 2021 Sep 16;13(9):1852. doi: 10.3390/v13091852.
Human noroviruses (HuNoVs) are the most common cause of viral gastroenteritis resulting annually in ~219,000 deaths and a societal cost of ~USD 60 billion, and no antivirals or vaccines are available. Here, we assess the anti-norovirus activity of new peptidomimetic aldehydes related to the protease inhibitor rupintrivir. The early hit compound inhibited the replication of murine norovirus (MNV) and the HuNoV GI.1 replicon in vitro (EC ~1 µM) and swiftly cleared the HuNoV GI.1 replicon from the cells. Compound still inhibits the proteolytic activity. We selected a resistant GI.1 replicon, with a mutation (I109V) in a highly conserved region of the viral protease, conferring a low yield of resistance against compound and rupintrivir. After testing new derivatives, compound was the most potent (EC nanomolar range). Molecular docking indicated that the aldehyde group of compounds and bind with Cys139 in the HuNoV 3CL protease by a covalent linkage. Finally, compound inhibited the replication of HuNoV GII.4 in infected zebrafish larvae, and PK studies in mice showed an adequate profile.
人类诺如病毒（HuNoVs）是病毒性肠胃炎的最常见病因，每年导致约 21.9 万人死亡和 600 亿美元的社会成本，且目前尚无抗病毒药物或疫苗。在此，我们评估了与蛋白酶抑制剂鲁匹那韦相关的新型拟肽醛类化合物的抗诺如病毒活性。早期命中化合物 抑制鼠诺如病毒（MNV）和 HuNoV GI.1 复制子的体外复制（EC 约 1 μM），并迅速从细胞中清除 HuNoV GI.1 复制子。化合物 仍抑制蛋白酶的活性。我们选择了一个具有突变（I109V）的耐药性 GI.1 复制子，该突变位于病毒蛋白酶的高度保守区域，对化合物 和鲁匹那韦的耐药性较低。在测试了新的衍生物后，化合物 是最有效的（EC 纳摩尔范围内）。分子对接表明，化合物 和 的醛基通过共价键与 HuNoV 3CL 蛋白酶的 Cys139 结合。最后，化合物 在感染的斑马鱼幼虫中抑制了 HuNoV GII.4 的复制，并且在小鼠中的 PK 研究表明其具有良好的特征。
