Volume 13 Issue 12
Dec.  2022
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Article Contents
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
Citation: 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

Targeting papain-like protease for broad-spectrum coronavirus inhibition

doi: 10.1007/s13238-022-00909-3
Funds:

the University of Hong Kong Outstanding Young Researcher Award

Hospital, Respiratory Viral Research Foundation Limited, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund Limited, Chan Yin Chuen Memorial Charitable Foundation, Marina Man-Wai Lee, the Hong Kong Hainan Commercial Association South China Microbiology Research Fund, the Jessie &

Theme-Based Research Scheme of the Research Grants Council (T11-709/21-N)

George Ho Charitable Foundation, Perfect Shape Medical Limited, Kai Chong Tong, Tse Kam Ming Laurence, Foo Oi Foundation Limited, Betty Hing-Chu Lee, Ping Cham So, and Lo Ying Shek Chi Wai Foundation. The funding sources had no role in the study design, data collection, analysis, interpretation or writing of the report. J.F.-W.C. has received travel grants from Pfizer Corporation Hong Kong and Astellas Pharma Hong Kong Corporation Limited, and was an invited speaker for Gilead Sciences Hong Kong Limited and Luminex Corporation. K.-Y.Y. report collaboration with Sinovac Biotech Ltd. and China National Pharmaceutical Group Co., Ltd. (Sinopharm). Patent application for the identified drug compounds in this study is in progress. All animal experiments were approved by the HKU Committee on the Use of Live Animals in Teaching and Research and were performed according to the standard operating procedures of the Biosafety Level 3 animal facilities. There was no human subject participated in this project.

the High Level-Hospital Program, Health Commission of Guangdong Province, China

the National Program on Key Research Project of China (2020YFA0707500 and 2020YFA0707504)

the University of Hong Kong Li Ka Shing Faculty of Medicine Research Output Prize

and donations of Shaw Foundation Hong Kong, Richard Yu and Carol Yu, Michael Seak-Kan Tong, May Tam Mak Mei Yin, Providence Foundation Limited (in memory of the late Lui Hac Minh), Lee Wan Keung Charity Foundation Limited, Hong Kong Sanatorium &

Emergency Key Program of Guangzhou Laboratory (EKPG22-01)

and the Swiss National Science Foundation, the National Research Programme "Covid-19" (No. 4078P0_198290/1)

Guangdong Natural Science Foundation (2022A1515010099)

This study was partly supported by funding from Health@InnoHK, Innovation and Technology Commission, the Government of the Hong Kong Special Administrative Region

the research project of Hainan Academician Innovation Platform (YSPTZX202004)

  • Received Date: 2021-09-01
  • Rev Recd Date: 2022-02-17
  • 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-of-concept 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.
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