Targeting papain-like protease for broad-spectrum coronavirus inhibition
Received date: 01 Sep 2021
Accepted date: 17 Feb 2022
Published date: 15 Dec 2022
Copyright
The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral therapeutics. Drugging the multi-functional papain-like protease (PLpro) domain of the viral nsp3 holds promise. However, none of the known coronavirus PLpro inhibitors has been shown to be in vivo active. Herein, we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity, including against the Sarbecoviruses (SARS-CoV-1 and SARS-CoV-2), Merbecovirus (MERS-CoV), as well as the Alphacoronavirus (hCoV-229E and hCoV-OC43). Importantly, F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice. F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage, as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase activity. Despite the significant difference of substrate recognition, mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue, whereas an allosteric inhibitor of MERS-PLpro interacting with its 271E position. Our proof-ofconcept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anti-coronavirus agents. The orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.
Key words： protease; inhibitor; coronavirus; Nsp3; antiviral
Shuofeng Yuan , Xiaopan Gao , Kaiming Tang , Jian-Piao Cai , Menglong Hu , Peng Luo , Lei Wen , Zi-Wei Ye , Cuiting Luo , Jessica Oi-Ling Tsang , Chris Chun-Yiu Chan , Yaoqiang Huang , Jianli Cao , Ronghui Liang , Zhenzhi Qin , Bo Qin , Feifei Yin , Hin Chu , Dong-Yan Jin , Ren Sun , Jasper Fuk-Woo Chan , Sheng Cui , Kwok-Yung Yuen . Targeting papain-like protease for broad-spectrum coronavirus inhibition[J]. Protein & Cell, 2022 , 13(12) : 940 -953 . DOI: 10.1007/s13238-022-00909-3
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