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.
摘要：
2019年冠状病毒病（COVID-19）是一种全身性疾病，可能在包括肝脏在内的多个组织中引起严重的代谢并发症，肾,和心血管系统。然而,潜在的机制和最佳治疗仍然难以捉摸。我们的研究表明，ACE2途径的损害是将病毒感染与其继发性代谢后遗症联系起来的关键因素。通过使用基于结构的高通量虚拟筛选和连接图数据库,随后进行了实验验证，我们确定了伊马替尼，醋甲唑胺,和harpagoside作为ACE2的直接酶活化剂。在胰岛素抵抗状态和SARS-CoV-2感染状态下，伊马替尼和醋甲唑胺以ACE2依赖性方式显着改善了体内代谢扰动。此外，由于ACE2与SARS-CoV-2上的刺突蛋白结合的变构抑制，这三种化合物直接抑制了病毒进入。一起来看,我们的研究表明，通过伊马替尼酶促激活ACE2，醋甲唑胺,或harpagoside可能是治疗COVID-19代谢后遗症的概念新策略。
