2. Academic Validation
  3. Imatinib and methazolamide ameliorate COVID-19-induced metabolic complications via elevating ACE2 enzymatic activity and inhibiting viral entry

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

  • Cell Metab. 2022 Mar 1;34(3):424-440.e7. doi: 10.1016/j.cmet.2022.01.008.
Zilun Li 1,  Meixiu Peng 2,  Pin Chen 3,  Chenshu Liu 4,  Ao Hu 5,  Yixin Zhang 5,  Jiangyun Peng 6,  Jiang Liu 7,  Yihui Li 7,  Wenxue Li 8,  Wei Zhu 8,  Dongxian Guan 9,  Yang Zhang 10,  Hongyin Chen 10,  Jiuzhou Li 10,  Dongxiao Fan 4,  Kan Huang 4,  Fen Lin 6,  Zefeng Zhang 6,  Zeling Guo 2,  Hengli Luo 6,  Xi He 11,  Yuanyuan Zhu 11,  Linghua Li 11,  Bingding Huang 12,  Weikang Cai 13,  Lei Gu 14,  Yutong Lu 3,  Kai Deng 15,  Li Yan 16,  Sifan Chen 17
Affiliations

Affiliations

  • 1 Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China. Electronic address: lizilun@mail.sysu.edu.cn.
  • 2 National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
  • 3 National Supercomputer Center in Guangzhou, School of Computer Science and Engineering, Sun Yat-Sen University, Guangzhou, Guangdong 510006, China.
  • 4 Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
  • 5 Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; Department of Immunology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
  • 6 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China.
  • 7 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China.
  • 8 Guangzhou Center for Disease Control and Prevention, Guangzhou, Guangdong 510440, China.
  • 9 Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 10 School of Public Health, Sun Yat-Sen University, Shenzhen, Guangdong 518107, China.
  • 11 Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510060, China.
  • 12 College of Big Data and Internet, Shenzhen Technology University, Shenzhen, Guangdong 518118, China.
  • 13 Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, NY 11568, USA.
  • 14 Max Planck Institute for Heart and Lung Research and Cardiopulmonary Institute (CPI), Bad Nauheim 61231, Germany.
  • 15 Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; Department of Immunology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China. Electronic address: dengkai6@mail.sysu.edu.cn.
  • 16 Department of Endocrinology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China. Electronic address: hfxyl@163.com.
  • 17 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China. Electronic address: chensf26@mail.sysu.edu.cn.
PMID: 35150639 DOI: 10.1016/j.cmet.2022.01.008
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.

Keywords

ACE2; COVID-19; SARS-CoV-2; enzymatic activator; harpagoside; imatinib; metabolic complication; methazolamide.

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