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

Ningke Hou, Lei Shuai, Lijing Zhang, Xuping Xie, Kaiming Tang, Yunkai Zhu, Yin Yu, Wenyi Zhang, Qiaozhu Tan, Gongxun Zhong, Zhiyuan Wen, Chong Wang, Xijun He, Hong Huo, Haishan Gao, You Xu, Jing Xue, Chen Peng, Jing Zou, Craig SchindewolfVineet Menachery, Wenji Su, Youlang Yuan, Zuyuan Shen, Rong Zhang, Shuofeng Yuan, Hongtao Yu, Pei Yong Shi, Zhigao Bu, Jing Huang, Qi Hu

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


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 EC50 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.

Original languageEnglish (US)
JournalACS Central Science
StateAccepted/In press - 2022

ASJC Scopus subject areas

  • General Chemistry
  • General Chemical Engineering


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