Imatinib and methazolamide ameliorate COVID-19-induced metabolic complications via elevating ACE2 enzymatic activity and inhibiting viral entry

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. [Display omitted] •ACE2 potentially links COVID-19 to its metabolic complications•Imatinib, methazolamide, and harpagoside are direct enzymatic activators of ACE2•Imatinib and methazolamide improve metabolic disorders under SARS-CoV-2 infection•These three compounds inhibit spike binding to ACE2 and reduce viral infection Li et al. identify imatinib and methazolamide as enzymatic activators of ACE2, which improve metabolic complications under SARS-CoV-2 infection and reduce viral entry via allosteric inhibition of binding between ACE2 and spike protein, suggesting that activation of ACE2 might be a conceptually new strategy to treat metabolic sequelae of COVID-19.