A study of Li et al

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 mechanism 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 insulin-resistant state and SARS-CoV-2-infected state. Moreover, the 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.