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对映体纯氯氟乙酰胺对新型冠状病毒主要蛋白酶的选择性共价靶向作用

Selective covalent targeting of SARS-CoV-2 main protease by enantiopure chlorofluoroacetamide.

作者信息

Yamane Daiki, Onitsuka Satsuki, Re Suyong, Isogai Hikaru, Hamada Rui, Hiramoto Tadanari, Kawanishi Eiji, Mizuguchi Kenji, Shindo Naoya, Ojida Akio

机构信息

Graduate School of Pharmaceutical Sciences, Kyushu University 3-1-1 Maidashi, Higashi-ku Fukuoka 812-8582 Japan

Artificial Intelligence Center for Health and Biomedical Research, National Institute of Biomedical Innovation, Health and Nutrition 7-6-8 Saito-Asagi, Ibaraki Osaka 567-0085 Japan.

出版信息

Chem Sci. 2022 Feb 15;13(10):3027-3034. doi: 10.1039/d1sc06596c. eCollection 2022 Mar 9.

DOI:10.1039/d1sc06596c
PMID:35432850
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8905997/
Abstract

The coronavirus disease 2019 (COVID-19) pandemic has necessitated the development of antiviral agents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The main protease (M) is a promising target for COVID-19 treatment. Here, we report an irreversible SARS-CoV-2 M inhibitor possessing chlorofluoroacetamide (CFA) as a warhead for the covalent modification of M. Ugi multicomponent reaction using chlorofluoroacetic acid enabled the rapid synthesis of dipeptidic CFA derivatives that identified 18 as a potent inhibitor of SARS-CoV-2 M. Among the four stereoisomers, (,)-18 exhibited a markedly higher inhibitory activity against M than the other isomers. Reaction kinetics and computational docking studies suggest that the configuration of the CFA warhead is crucial for the rapid covalent inhibition of M. Our findings highlight the prominent influence of the CFA chirality on the covalent modification of proteinous cysteines and provide the basis for improving the potency and selectivity of CFA-based covalent inhibitors.

摘要

2019年冠状病毒病（COVID-19）大流行促使人们研发针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的抗病毒药物。主要蛋白酶（M）是COVID-19治疗的一个有前景的靶点。在此，我们报道了一种不可逆的SARS-CoV-2 M抑制剂，其具有氯氟乙酰胺（CFA）作为用于M共价修饰的弹头。使用氯氟乙酸的乌吉多组分反应能够快速合成二肽CFA衍生物，其中18被鉴定为SARS-CoV-2 M的有效抑制剂。在四种立体异构体中，（，）-18对M的抑制活性明显高于其他异构体。反应动力学和计算对接研究表明，CFA弹头的构型对于M的快速共价抑制至关重要。我们的研究结果突出了CFA手性对蛋白质半胱氨酸共价修饰的显著影响，并为提高基于CFA的共价抑制剂的效力和选择性提供了基础。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a3f7/8905997/9b222639ea58/d1sc06596c-f5.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a3f7/8905997/9a3a0cc49727/d1sc06596c-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a3f7/8905997/9b222639ea58/d1sc06596c-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a3f7/8905997/580b5ea4548a/d1sc06596c-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a3f7/8905997/4661bcb7740b/d1sc06596c-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a3f7/8905997/6248fd49e25f/d1sc06596c-f3.jpg
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