3CL Protease Inhibitors with an Electrophilic Arylketone Moiety as Anti-SARS-CoV-2 Agents
3CL Protease Inhibitors with an Electrophilic Arylketone Moiety as Anti-SARS-CoV-2 Agents
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DOI：
10.1021/acs.jmedchem.1c00665
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发表时间：
2022-02-24
影响因子：
7.3
通讯作者：
Hayashi, Yoshio
中科院分区：
文献类型：
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作者：
Konno, Sho;Kobayashi, Kiyotaka;Hayashi, Yoshio
新型冠状病毒SARS-CoV-2已被确定为当前冠状病毒病(新冠肺炎)大流行的病原体。3CL蛋白酶(3CL(Pro))在病毒多蛋白的加工过程中起着关键作用。我们报道了含有独特的苯并噻唑基酮的模拟肽化合物，它们具有很强的抗SARS-CoV-2 3CL(Pro)活性。其中作用最强的YH-53能较强地阻断SARS-CoV-2的复制。X-射线结构分析表明，YH-53与主链氨基酸建立了多个氢键相互作用，与活性中心3CL(Pro)建立了共价键。计算和实验研究的进一步结果，包括YH-53的体外吸收、分布、代谢和排泄、体内药代动力学和代谢分析，表明它有很高的潜力成为与新冠肺炎竞争的主要候选药物。
The novel coronavirus, SARS-CoV-2, has been identified as the causative agent for the current coronavirus disease (COVID-19) pandemic. 3CL protease (3CL(pro)) plays a pivotal role in the processing of viral polyproteins. We report peptidomimetic compounds with a unique benzothiazolyl ketone as a warhead group, which display potent activity against SARS-CoV-2 3CL(pro). The most potent inhibitor YH-53 can strongly block the SARS-CoV-2 replication. X-ray structural analysis revealed that YH-53 establishes multiple hydrogen bond interactions with backbone amino acids and a covalent bond with the active site of 3CL(pro). Further results from computational and experimental studies, including an in vitro absorption, distribution, metabolism, and excretion profile, in vivo pharmacokinetics, and metabolic analysis of YH-53 suggest that it has a high potential as a lead candidate to compete with COVID-19.