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Cell Metab ; 34(3): 424-440.e7, 2022 03 01.
Article in English | MEDLINE | ID: covidwho-1676683

ABSTRACT

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.


Subject(s)
COVID-19/drug therapy , Imatinib Mesylate/therapeutic use , Metabolic Diseases/drug therapy , Methazolamide/therapeutic use , SARS-CoV-2/drug effects , Angiotensin-Converting Enzyme 2/drug effects , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/complications , COVID-19/metabolism , COVID-19/virology , Cells, Cultured , Chlorocebus aethiops , Down-Regulation/drug effects , HEK293 Cells , Human Umbilical Vein Endothelial Cells , Humans , Imatinib Mesylate/pharmacology , Male , Metabolic Diseases/metabolism , Metabolic Diseases/virology , Methazolamide/pharmacology , Mice , Mice, Inbred C57BL , Mice, Obese , Mice, Transgenic , SARS-CoV-2/physiology , Vero Cells , Virus Internalization/drug effects
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