Cell Metabolism. 2022 Feb 11
Zilun Li, Meixiu Peng, Pin Chen, Chenshu Liu, Ao Hu, Yixin Zhang, Jiangyun Peng, Jiang Liu, Yihui Li, Wenxue Li, Wei Zhu, Dongxian Guan, Yang Zhang, Hongyin Chen, Jiuzhou Li, Dongxiao Fan, Kan Huang, Fen Lin, Zefeng Zhang, Zeling Guo, Hengli Luo, Xi He, Yuanyuan Zhu, Linghua Li, Bingding Huang, Weikang Cai, Lei Gu, Yutong Lu, Kai Deng,Li Yan, and Sifan Chen
Products used in the paper Details Operation
HEK293T/ACE2 stable cell line; SARS-CoV-2
HEK293T/ACE2 stable cell line (PackGene Biotech, China), which is constructed by transduction of human ACE2 (hACE2) into HEK293T cells, were pretreated with imatinib, harpagoside, or methazolamide for 6 h, respectively. Subsequently, SARS-CoV-2 pseudovirions (PackGene Biotech, China) were added to the cells and incubated at 37C for another 66 h. Request Quote

Research Field: Covid-related

Keywords: COVID-19, SARS-CoV-2, ACE2, metabolic complication, enzymatic activator, imatinib, methazolamide, harpagoside


Coronavirus disease 2019 (COVID-19) represents a systemic disease that may cause severe metabolic complications in multiple tissues including liver, kidney, and cardiovascular system. However, the underlying mechanisms and optimal treatment remain elusive. Our study shows that impairment of ACE2 pathway is a key factor linking virus infection to its secondary metabolic sequelae. By using structure-based high-throughput virtual screening and connectivity map database, followed with experimental validations, we identify imatinib, methazolamide, and harpagoside as direct enzymatic activators of ACE2. Imatinib and methazolamide remarkably improve metabolic perturbations in vivo in an ACE2-dependent manner under the insulin-resistant state and SARS-CoV-2-infected state. Moreover, viral entry is directly inhibited by these three compounds due to allosteric inhibition of ACE2 binding to spike protein on SARS-CoV-2. Taken together, our study shows that enzymatic activation of ACE2 via imatinib, methazolamide, or harpagoside may be a conceptually new strategy to treat metabolic sequelae of COVID-19.

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