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

Zilun Li; Meixiu Peng; Pin Chen; Chenshu Liu; Ao Hu; Yixin Zhang; Jiangyun Peng; Jiang Liu; Yihui Li; Wenxue Li; Wei Zhu; Dongxian Guan; Yang Zhang; Hongyin Chen; Jiuzhou Li; Dongxiao Fan; Kan Huang; Fen Lin; Zefeng Zhang; Zeling Guo; Hengli Luo; Xi He; Yuanyuan Zhu; Linghua Li; Bingding Huang; Weikang Cai; Lei Gu; Yutong Lu; Kai Deng; Li Yan; Sifan Chen

doi:10.1016/j.cmet.2022.01.008

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

Zilun Li, Meixiu Peng, Pin Chen, Chenshu Liu, Ao Hu, Yixin Zhang, Jiangyun Peng, Jiang Liu, Yihui Li, Wenxue Li, Wei Zhu, Dongxian Guan, Yang Zhang, Hongyin Chen, Jiuzhou Li, Dongxiao Fan, Kan Huang, Fen Lin, Zefeng Zhang, Zeling GuoHengli Luo, Xi He, Yuanyuan Zhu, Linghua Li, Bingding Huang, Weikang Cai, Lei Gu, Yutong Lu, Kai Deng, Li Yan, Sifan Chen

Molecular and Cellular Biochemistry

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

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.

Original language	English
Pages (from-to)	424-440.e7
Journal	Cell Metabolism
Volume	34
Issue number	3
DOIs	https://doi.org/10.1016/j.cmet.2022.01.008
State	Published - Mar 1 2022

Bibliographical note

Publisher Copyright:
© 2022 Elsevier Inc.

Funding

We thank Prof. Hui Zhang's lab (Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University) for providing the SARS-CoV-2 virus strain. This study was supported by the Guangdong Science and Technology Department (2020B1212060018, 2020B1212030004) and the special COVID-19 grant from the Project of Educational Commission of Guangdong Province of China (no. 2020KZDXZ1215). The funders had no role in study design, data collection and analysis, or preparation of the manuscript. Z.L. M.P. C.L. A.H. Yixin Zhang. J.P. H.C. J. Li, D.F. K.H. and S.C. performed the experiments; P.C. Y. Lu, and M.P. performed compound screening; J. Liu, Y. Li, W.L. W.Z. Yang Zhang, F.L. Z.Z. Z.G. and H.L. provided technical support; D.G. X.H. Y. Zhu, L.L. B.H. W.C. L.G. and L.Y. provided materials; D.G. B.H. W.C. L.G. and L.Y. discussed the project; and Z.L. M.P. P.C. C.L. K.D. L.Y. and S.C. wrote and edited the manuscript. S.C. conceived of the project idea. The authors declare no competing interests. We thank Prof. Hui Zhang’s lab (Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University) for providing the SARS-CoV-2 virus strain. This study was supported by the Guangdong Science and Technology Department ( 2020B1212060018 , 2020B1212030004 ) and the special COVID-19 grant from the Project of Educational Commission of Guangdong Province of China (no. 2020KZDXZ1215 ). The funders had no role in study design, data collection and analysis, or preparation of the manuscript.

Funders	Funder number
Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University
Project of Educational Commission of Guangdong Province of China	2020KZDXZ1215
Eunice Kennedy Shriver National Institute of Child Health and Human Development	P50HD105351
Eunice Kennedy Shriver National Institute of Child Health and Human Development
Guangdong Science and Technology Department	2020B1212030004, 2020B1212060018
Guangdong Science and Technology Department

Keywords

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

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

Access to Document

10.1016/j.cmet.2022.01.008

Cite this

Li, Z., Peng, M., Chen, P., Liu, C., Hu, A., Zhang, Y., Peng, J., Liu, J., Li, Y., Li, W., Zhu, W., Guan, D., Zhang, Y., Chen, H., Li, J., Fan, D., Huang, K., Lin, F., Zhang, Z., ... Chen, S. (2022). Imatinib and methazolamide ameliorate COVID-19-induced metabolic complications via elevating ACE2 enzymatic activity and inhibiting viral entry. Cell Metabolism, 34(3), 424-440.e7. https://doi.org/10.1016/j.cmet.2022.01.008

@article{4f4229fa84cb430dab81ba45e7253e41,

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

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, enzymatic activator, harpagoside, imatinib, metabolic complication, methazolamide, SARS-CoV-2",

author = "Zilun Li and Meixiu Peng and Pin Chen and Chenshu Liu and Ao Hu and Yixin Zhang and Jiangyun Peng and Jiang Liu and Yihui Li and Wenxue Li and Wei Zhu and Dongxian Guan and Yang Zhang and Hongyin Chen and Jiuzhou Li and Dongxiao Fan and Kan Huang and Fen Lin and Zefeng Zhang and Zeling Guo and Hengli Luo and Xi He and Yuanyuan Zhu and Linghua Li and Bingding Huang and Weikang Cai and Lei Gu and Yutong Lu and Kai Deng and Li Yan and Sifan Chen",

note = "Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",

year = "2022",

month = mar,

day = "1",

doi = "10.1016/j.cmet.2022.01.008",

language = "English",

volume = "34",

pages = "424--440.e7",

number = "3",

}

Li, Z, Peng, M, Chen, P, Liu, C, Hu, A, Zhang, Y, Peng, J, Liu, J, Li, Y, Li, W, Zhu, W, Guan, D, Zhang, Y, Chen, H, Li, J, Fan, D, Huang, K, Lin, F, Zhang, Z, Guo, Z, Luo, H, He, X, Zhu, Y, Li, L, Huang, B, Cai, W, Gu, L, Lu, Y, Deng, K, Yan, L & Chen, S 2022, 'Imatinib and methazolamide ameliorate COVID-19-induced metabolic complications via elevating ACE2 enzymatic activity and inhibiting viral entry', Cell Metabolism, vol. 34, no. 3, pp. 424-440.e7. https://doi.org/10.1016/j.cmet.2022.01.008

TY - JOUR

T1 - Imatinib and methazolamide ameliorate COVID-19-induced metabolic complications via elevating ACE2 enzymatic activity and inhibiting viral entry

AU - Li, Zilun

AU - Peng, Meixiu

AU - Chen, Pin

AU - Liu, Chenshu

AU - Hu, Ao

AU - Zhang, Yixin

AU - Peng, Jiangyun

AU - Liu, Jiang

AU - Li, Yihui

AU - Li, Wenxue

AU - Zhu, Wei

AU - Guan, Dongxian

AU - Zhang, Yang

AU - Chen, Hongyin

AU - Li, Jiuzhou

AU - Fan, Dongxiao

AU - Huang, Kan

AU - Lin, Fen

AU - Zhang, Zefeng

AU - Guo, Zeling

AU - Luo, Hengli

AU - He, Xi

AU - Zhu, Yuanyuan

AU - Li, Linghua

AU - Huang, Bingding

AU - Cai, Weikang

AU - Gu, Lei

AU - Lu, Yutong

AU - Deng, Kai

AU - Yan, Li

AU - Chen, Sifan

PY - 2022/3/1

Y1 - 2022/3/1

N2 - 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.

AB - 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.

KW - ACE2

KW - COVID-19

KW - enzymatic activator

KW - harpagoside

KW - imatinib

KW - metabolic complication

KW - methazolamide

KW - SARS-CoV-2

UR - http://www.scopus.com/inward/record.url?scp=85125241579&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85125241579&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2022.01.008

DO - 10.1016/j.cmet.2022.01.008

M3 - Article

C2 - 35150639

AN - SCOPUS:85125241579

SN - 1550-4131

VL - 34

SP - 424-440.e7

JO - Cell Metabolism

JF - Cell Metabolism

IS - 3

ER -

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this