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

Li, Z., Peng, M., Chen, P., Liu, C., Hu, A., Zhang, Y., et al. (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. doi:10.1016/j.cmet.2022.01.008.

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 Creators:
Li, Zilun, Author
Peng, Meixiu, Author
Chen, Pin, Author
Liu, Chenshu, Author
Hu, Ao, Author
Zhang, Yixin, Author
Peng, Jiangyun, Author
Liu, Jiang, Author
Li, Yihui, Author
Li, Wenxue, Author
Zhu, Wei, Author
Guan, Dongxian, Author
Zhang, Yang, Author
Chen, Hongyin, Author
Li, Jiuzhou, Author
Fan, Dongxiao, Author
Huang, Kan, Author
Lin, Fen, Author
Zhang, Zefeng, Author
Guo, Zeling, Author
Luo, Hengli, AuthorHe, Xi, AuthorZhu, Yuanyuan, AuthorLi, Linghua, AuthorHuang, Bingding, AuthorCai, Weikang, AuthorGu, Lei1, Author              Lu, Yutong, AuthorDeng, Kai, AuthorYan, Li, AuthorChen, Sifan, Author more..
Affiliations:
1Epigenetics, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_3327072              

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 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.

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 Dates: 2022-02-112022-03-01
 Publication Status: Published in print
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 Rev. Type: -
 Identifiers: ISI: 000764898700008
DOI: 10.1016/j.cmet.2022.01.008
PMID: 35150639
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Title: CELL METABOLISM
Source Genre: Journal
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Pages: - Volume / Issue: 34 (3) Sequence Number: - Start / End Page: 424 - 440 Identifier: ISSN: 1550-4131