Cell Metabolism Sun Yat-sen University Chen Sifan/Yan Li/Deng Kai/Li Zilun found that drugs such as imatinib can improve metabolic complications induced by new coronavirus infection

iNature Coronavirus disease 2019 (COVID-19) is a systemic disease that can cause severe metabolic complications in multiple tissues including the liver, kidneys and cardiovascular system
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However, the underlying mechanisms and optimal treatments remain elusive
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On February 11, 2022, Sun Yat-Sen University, Chen Sifan, Yan Li, Deng Kai and Li Zilun, published a joint communication online in Cell Metabolism entitled "Imatinib and methazolamide ameliorate COVID-19-induced metabolic complications via elevating ACE2 enzymatic activity and inhibiting viral entry" , which showed that impairment of the ACE2 pathway is a key factor linking viral infection to its secondary metabolic sequelae
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Using a structure-based high-throughput virtual screening and linkage map database, followed by experimental validation, this study identified imatinib, methazolamide, and harpagoside as direct enzymatic activators of ACE2
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Imatinib and methazolamide significantly ameliorated metabolic perturbations in vivo in an ACE2-dependent manner under insulin resistance and SARS-CoV-2 infection
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Furthermore, these three compounds directly inhibit viral entry due to allosteric inhibition of ACE2 binding to the spike protein on SARS-CoV-2
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In conclusion, this study suggests that enzymatic activation of ACE2 by imatinib, methazolamide, or harpagoside may be a conceptual new strategy for the treatment of metabolic sequelae of COVID-19
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Coronavirus disease 2019 (COVID-19) is a systemic disease that severely disrupts multiple tissues and organs throughout the body
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Notably, emerging evidence suggests that SARS-CoV-2 infection promotes systemic and organ-level metabolic complications, including hyperglycemia, hypertension, and low HDL cholesterol, in patients without pre-existing metabolic disease Systemic metabolic defects including HDL-C have been widely reported
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"New-onset" diabetes has been reported in 5%–29% of COVID-19 patients and is associated with worse outcomes
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Metabolic deficits known to be associated with COVID-19 at the organ level include hepatic steatosis, glomerulopathy, endothelial dysfunction, and thrombosis
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Supporting this, proteomic analysis of autopsy samples revealed dysregulation of glucose and fatty acid metabolism in multiple organs, including liver, kidney, and heart
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Overall, SARS-CoV-2 may cause severe metabolic deficits and/or long-term complications
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However, the key mechanisms mediating the deleterious metabolic effects of SARS-CoV-2 remain largely unknown
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Here, the study performed an omics analysis to identify differentially expressed genes between COVID-19 and metabolic diseases, including diabetes, hypertension, diabetic nephropathy, and atherosclerosis
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Surprisingly, this study identified downregulation of ACE2 as the best candidate protein that might mediate SARS-CoV-2-induced metabolic defects
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This study combines connectivity map (CMAP), supercomputer-based docking, and experimental approaches to identify potential strategies for restoring the damaged ACE2 pathway
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The study identified three new ACE2 enzyme activators: imatinib, methazolamide, and harpagoside
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Two repurposed drugs, imatinib and methazolamide, can act as ACE2 enzyme activators and effectively improve glucose and lipid metabolism after SARS-CoV-2 infection in vivo
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In addition, imatinib and methazolamide showed direct antiviral effects by inhibiting the binding of ACE2 to the spike protein
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Given the very limited understanding of SARS-CoV-2 pathology and the lack of effective therapies for COVID-19 and its metabolic complications, this repurposed drug may hold promise for rapid clinical application in this emergency setting treatment candidates
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