Repurposing Halicin as a potent covalent inhibitor for the SARS-CoV-2 main protease

Current research in chemical biology Pub Date : 2022-01-01 DOI:10.1016/j.crchbi.2022.100025

Kai S. Yang , Syuan-Ting Alex Kuo , Lauren R. Blankenship , Zhi Zachary Geng , Shuhua G. Li , David H. Russell , Xin Yan , Shiqing Xu , Wenshe Ray Liu

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引用次数: 6

Abstract

The rapid spread of COVID-19 has caused a worldwide public health crisis. For prompt and effective development of antivirals for SARS-CoV-2, the pathogen of COVID-19, drug repurposing has been broadly conducted by targeting the main protease (M^Pro), a key enzyme responsible for the replication of virus inside the host. In this study, we evaluate the inhibition potency of a nitrothiazole-containing drug, halicin, and reveal its reaction and interaction mechanism with M^Pro. The in vitro potency test shows that halicin inhibits the activity of M^Pro an IC₅₀ of 181.7 nM. Native mass spectrometry and X-ray crystallography studies clearly indicate that the nitrothiazole fragment of halicin covalently binds to the catalytic cysteine C145 of M^Pro. Interaction and conformational changes inside the active site of M^Pro suggest a favorable nucleophilic aromatic substitution reaction mechanism between M^Pro C145 and halicin, explaining the high inhibition potency of halicin towards M^Pro.

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重新利用Halicin作为SARS-CoV-2主要蛋白酶的有效共价抑制剂

2019冠状病毒病的快速传播已造成全球公共卫生危机。为了及时有效地开发针对COVID-19病原体SARS-CoV-2的抗病毒药物，药物重新利用已广泛地针对宿主内负责病毒复制的关键酶主蛋白酶(MPro)进行。在这项研究中，我们评估了一种含硝基噻唑的药物halicin的抑制能力，并揭示了它与MPro的反应和相互作用机制。体外效价试验表明，halicin抑制MPro活性，IC50为181.7 nM。原生质谱和x射线晶体学研究清楚地表明，halicin的硝基噻唑片段与MPro的催化半胱氨酸C145共价结合。MPro活性位点内的相互作用和构象变化表明，MPro C145与halicin之间存在良好的亲核芳香取代反应机制，这解释了halicin对MPro具有较高的抑制作用。

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来源期刊

Current research in chemical biology Biochemistry, Genetics and Molecular Biology (General)

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56 days