Bisubstrate Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 Nsp14 Methyltransferase.
Bisubstrate Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 Nsp14 Methyltransferase.
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DOI：
10.1021/acsmedchemlett.2c00265
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发表时间：
2022-09-08
影响因子：
4.2
通讯作者：
Chen, Liqiang
中科院分区：
文献类型：
--
作者：
Jung, Eunkyung;Soto-Acosta, Ruben;Xie, Jiashu;Wilson, Daniel J.;Dreis, Christine D.;Majima, Ryuichi;Edwards, Tiffany C.;Geraghty, Robert J.;Chen, Liqiang
利用新冠病毒（SARS-CoV - 2）Nsp14甲基转移酶独特的狭窄活性位点，我们设计了与S - 腺苷甲硫氨酸（SAM）和RNA底物结合口袋相互作用的双底物抑制剂。我们的努力得到了纳摩尔级的抑制剂，包括化合物3和10。作为一种原型抑制剂，化合物3相对于一组人类甲基转移酶也具有出色的选择性。值得注意的是，C - 核苷10表现出高抗病毒活性和低细胞毒性，导致治疗指数（半数细胞毒性浓度CC50 / 半数有效浓度EC50）大于139。此外，对这两种化合物的简要代谢分析表明，它们不太可能存在重大代谢缺陷。而且，计算机对接研究指出了可用于增强抑制活性的蛋白质 - ligand相互作用。简而言之，抑制剂10的发现清楚地表明，通过靶向Nsp14甲基转移酶可以实现强大且选择性的抗新冠病毒活性。因此，当前的工作有力地支持继续研发Nsp14甲基转移酶抑制剂作为新冠（COVID - 19）治疗药物。
Taking advantage of the uniquely constricted active site of SARS-CoV-2 Nsp14 methyltransferase, we have designed bisubstrate inhibitors interacting with the SAM and RNA substrate binding pockets. Our efforts have led to nanomolar inhibitors including compounds 3 and 10. As a prototypic inhibitor, compound 3 also has an excellent selectivity profile over a panel of human methyltransferases. Remarkably, C-nucleoside 10 exhibits high antiviral activity and low cytotoxicity, leading to a therapeutic index (CC50/EC50) greater than 139. Furthermore, a brief metabolic profiling of these two compounds suggests that they are less likely to suffer from major metabolic liabilities. Moreover, computational docking studies point to protein–ligand interactions that can be exploited to enhance inhibitory activity. In short, discovery of inhibitor 10 clearly demonstrates that potent and selective anti-SARS-CoV-2 activity can be achieved by targeting the Nsp14 methyltransferase. Therefore, the current work strongly supports the continued pursuit of Nsp14 methyltransferase inhibitors as COVID-19 therapeutics.
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DOI：
10.1073/pnas.2101161118
发表时间：
2021-06-15
影响因子：
11.1
作者：
Hsu JC;Laurent-Rolle M;Pawlak JB;Wilen CB;Cresswell P
通讯作者：
Cresswell P
影响因子：
6.7
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影响因子：
3.7
作者：
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Balimane, Praveen V.
影响因子：
1.8
作者：
Liu, F;Austin, DJ
通讯作者：
Austin, DJ
影响因子：
1.8
作者：
Metobo, Sammy E.;Xu, Jie;Kim, Choung U.
通讯作者：
Kim, Choung U.