Exploring diverse reactive warheads for the design of SARS-CoV-2 main protease inhibitors.
Exploring diverse reactive warheads for the design of SARS-CoV-2 main protease inhibitors.
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DOI：
10.1016/j.ejmech.2023.115667
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发表时间：
2023-07
影响因子：
6.7
通讯作者：
Bin Tan;M. Sacco;Hao Tan;Kan Li;Ryan Joyce;Xiujun Zhang;Yu Chen;Jun Wang
中科院分区：
文献类型：
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作者：
Bin Tan;M. Sacco;Hao Tan;Kan Li;Ryan Joyce;Xiujun Zhang;Yu Chen;Jun Wang
SARS-CoV-2主要蛋白酶（Mpro）是辉瑞公司口服药物Paxlovid中的活性成分Nirmatrelvir的经验证的抗病毒药物靶标。药物相互作用限制了Paxlovid的使用。此外，已从细胞培养物病毒传代和天然存在的变体中鉴定出抗nirmatrelvir的耐药Mpromutants。因此，需要第二代Mpro抑制剂。在这项研究中，我们探讨了几个反应弹头的设计Mproinhibitors。我们确认了Jun 11119 R（乙烯基磺酰胺弹头），Jun 10221 R（丙酰胺弹头），Jun 1112 R（4-氯丁-2-酰脲弹头），Jun 10541 R（腈弹头）和Jun 10963 R Jun 10541 RandJun 10963 R在Calu-3细胞中对SARS-CoV-2也具有有效的抗病毒活性，EC 50值为2.92和6.47 μM，分别Mpro与Jun 10541 RandJun 10221的X射线晶体结构显示Cys 145的共价修饰。这些具有不同反应弹头的Mpro抑制剂共同代表了进一步开发的有希望的候选者。
SARS-CoV-2 main protease (Mpro) is a validated antiviral drug target of nirmatrelvir, the active ingredient in Pfizer's oral drug Paxlovid. Drug-drug interactions limit the use of Paxlovid. In addition, drug-resistant Mpromutants against nirmatrelvir have been identified from cell culture viral passage and naturally occurring variants. As such, there is a need for a second generation of Mproinhibitors. In this study, we explored several reactive warheads in the design of Mproinhibitors. We identifiedJun11119R(vinyl sulfonamide warhead),Jun10221R(propiolamide warhead),Jun1112R(4-chlorobut-2-ynamide warhead),Jun10541R(nitrile warhead), andJun10963R(dually activated nitrile warhead) as potent Mproinhibitors.Jun10541RandJun10963Ralso had potent antiviral activity against SARS-CoV-2 in Calu-3 cells with EC50values of 2.92 and 6.47 μM, respectively. X-ray crystal structures of MprowithJun10541RandJun10221revealed covalent modification of Cys145. These Mproinhibitors with diverse reactive warheads collectively represent promising candidates for further development.