Cross-linking peptide and repurposed drugs inhibit both entry pathways of SARS-CoV-2
Hanjun Zhao, Kelvin Kai‐Wang To, Hoiyan Lam, Xinxin Zhou, Jasper Fuk‐Woo Chan, Peng Zheng, Andrew Chak-Yiu Lee, Jian‐Piao Cai, Wan-Mui Chan, Jonathan Daniel Ip, Chris Chung‐Sing Chan, Man Lung Yeung, Jinxia Zhang, Allen Wing Ho Chu, Shibo Jiang, Kwok‐Yung Yuen
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.