Cross-linking peptide and repurposed drugs inhibit both entry pathways of SARS-CoV-2

Hanjun Zhao, Kelvin K. W. To, Hoiyan Lam, Xinxin Zhou, Jasper Fuk-Woo Chan, Zheng Peng, Andrew C. Y. Lee, Jianpiao Cai, Wan-Mui Chan, Jonathan Daniel Ip, Chris Chung-Sing Chan, Man Lung Yeung, Anna Jinxia Zhang, Allen Wing Ho Chu, Shibo Jiang and Kwok-Yung Yuen ()
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Hanjun Zhao: Li Ka Shing Faculty of Medicine, The University of Hong Kong
Kelvin K. W. To: Li Ka Shing Faculty of Medicine, The University of Hong Kong
Hoiyan Lam: Li Ka Shing Faculty of Medicine, The University of Hong Kong
Xinxin Zhou: Li Ka Shing Faculty of Medicine, The University of Hong Kong
Jasper Fuk-Woo Chan: Li Ka Shing Faculty of Medicine, The University of Hong Kong
Zheng Peng: Li Ka Shing Faculty of Medicine, The University of Hong Kong
Andrew C. Y. Lee: Li Ka Shing Faculty of Medicine, The University of Hong Kong
Jianpiao Cai: Li Ka Shing Faculty of Medicine, The University of Hong Kong
Wan-Mui Chan: Li Ka Shing Faculty of Medicine, The University of Hong Kong
Jonathan Daniel Ip: Li Ka Shing Faculty of Medicine, The University of Hong Kong
Chris Chung-Sing Chan: Li Ka Shing Faculty of Medicine, The University of Hong Kong
Man Lung Yeung: Li Ka Shing Faculty of Medicine, The University of Hong Kong
Anna Jinxia Zhang: Li Ka Shing Faculty of Medicine, The University of Hong Kong
Allen Wing Ho Chu: Li Ka Shing Faculty of Medicine, The University of Hong Kong
Shibo Jiang: Fudan University
Kwok-Yung Yuen: Li Ka Shing Faculty of Medicine, The University of Hong Kong

Nature Communications, 2021, vol. 12, issue 1, 1-9

Abstract: Abstract Up to date, effective antivirals have not been widely available for treating COVID-19. In this study, we identify a dual-functional cross-linking peptide 8P9R which can inhibit the two entry pathways (endocytic pathway and TMPRSS2-mediated surface pathway) of SARS-CoV-2 in cells. The endosomal acidification inhibitors (8P9R and chloroquine) can synergistically enhance the activity of arbidol, a spike-ACE2 fusion inhibitor, against SARS-CoV-2 and SARS-CoV in cells. In vivo studies indicate that 8P9R or the combination of repurposed drugs (umifenovir also known as arbidol, chloroquine and camostat which is a TMPRSS2 inhibitor), simultaneously interfering with the two entry pathways of coronaviruses, can significantly suppress SARS-CoV-2 replication in hamsters and SARS-CoV in mice. Here, we use drug combination (arbidol, chloroquine, and camostat) and a dual-functional 8P9R to demonstrate that blocking the two entry pathways of coronavirus can be a promising and achievable approach for inhibiting SARS-CoV-2 replication in vivo. Cocktail therapy of these drug combinations should be considered in treatment trials for COVID-19.

Date: 2021
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DOI: 10.1038/s41467-021-21825-w

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