Development of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 3CLpro

[Image: see text] The 3C-like protease (3CLpro) is an essential enzyme for the replication of SARS-CoV-2 and other coronaviruses and thus is a target for coronavirus drug discovery. Nearly all inhibitors of coronavirus 3CLpro reported so far are covalent inhibitors. Here, we report the development o...

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Detalles Bibliográficos
Autores principales: Hou, Ningke, Shuai, Lei, Zhang, Lijing, Xie, Xuping, Tang, Kaiming, Zhu, Yunkai, Yu, Yin, Zhang, Wenyi, Tan, Qiaozhu, Zhong, Gongxun, Wen, Zhiyuan, Wang, Chong, He, Xijun, Huo, Hong, Gao, Haishan, Xu, You, Xue, Jing, Peng, Chen, Zou, Jing, Schindewolf, Craig, Menachery, Vineet, Su, Wenji, Yuan, Youlang, Shen, Zuyuan, Zhang, Rong, Yuan, Shuofeng, Yu, Hongtao, Shi, Pei-Yong, Bu, Zhigao, Huang, Jing, Hu, Qi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9885526/
https://www.ncbi.nlm.nih.gov/pubmed/36844503
http://dx.doi.org/10.1021/acscentsci.2c01359
Descripción
Sumario:[Image: see text] The 3C-like protease (3CLpro) is an essential enzyme for the replication of SARS-CoV-2 and other coronaviruses and thus is a target for coronavirus drug discovery. Nearly all inhibitors of coronavirus 3CLpro reported so far are covalent inhibitors. Here, we report the development of specific, noncovalent inhibitors of 3CLpro. The most potent one, WU-04, effectively blocks SARS-CoV-2 replications in human cells with EC(50) values in the 10-nM range. WU-04 also inhibits the 3CLpro of SARS-CoV and MERS-CoV with high potency, indicating that it is a pan-inhibitor of coronavirus 3CLpro. WU-04 showed anti-SARS-CoV-2 activity similar to that of PF-07321332 (Nirmatrelvir) in K18-hACE2 mice when the same dose was administered orally. Thus, WU-04 is a promising drug candidate for coronavirus treatment.

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