Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease
Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease
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DOI：
10.1126/science.abb4489
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发表时间：
2020-06-19
期刊：
影响因子：
56.9
通讯作者：
Liu, Hong
中科院分区：
文献类型：
--
作者：
Dai, Wenhao;Zhang, Bing;Liu, Hong
SARS-CoV-2（严重急性呼吸综合征冠状病毒2型）是导致全球COVID-19（2019冠状病毒病）爆发的病原体。SARS-CoV-2的主要蛋白酶M-pro是介导病毒复制和转录的关键酶。我们设计并合成了两个以M-pro为靶点的先导化合物（11 a和11b）。这两种化合物均具有良好的抑制活性和有效的抗SARS-CoV-2感染活性。SARS-CoV-2 M-pro与11 a或11b复合物的X射线晶体结构均以1.5埃的分辨率测定，表明11 a和11b的醛基与M-pro的半胱氨酸145共价结合。这两种化合物在体内均表现出良好的药代动力学性质，并且11 a也表现出低毒性，这表明这些化合物是有希望的候选药物。
SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, M-pro, is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (11a and 11b) targeting M-pro. Both exhibited excellent inhibitory activity and potent anti-SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 M-pro in complex with 11a or 11b, both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of 11a and 11b are covalently bound to cysteine 145 of M-pro. Both compounds showed good pharmacokinetic properties in vivo, and 11a also exhibited low toxicity, which suggests that these compounds are promising drug candidates.