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Tytuł:
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Repositioning of histamine H 1 receptor antagonist: Doxepin inhibits viropexis of SARS-CoV-2 Spike pseudovirus by blocking ACE2.
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Autorzy:
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Ge S; School of Pharmacy, Xi'an Jiaotong University, Yanta West Road No.76, Xi'an, Shaanxi, 710061 China.
Wang X; School of Pharmacy, Xi'an Jiaotong University, Yanta West Road No.76, Xi'an, Shaanxi, 710061 China.
Hou Y; School of Pharmacy, Xi'an Jiaotong University, Yanta West Road No.76, Xi'an, Shaanxi, 710061 China.
Lv Y; School of Pharmacy, Xi'an Jiaotong University, Yanta West Road No.76, Xi'an, Shaanxi, 710061 China.
Wang C; School of Pharmacy, Xi'an Jiaotong University, Yanta West Road No.76, Xi'an, Shaanxi, 710061 China.
He H; School of Pharmacy, Xi'an Jiaotong University, Yanta West Road No.76, Xi'an, Shaanxi, 710061 China. Electronic address: .
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Źródło:
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European journal of pharmacology [Eur J Pharmacol] 2021 Apr 05; Vol. 896, pp. 173897. Date of Electronic Publication: 2021 Jan 23.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Publication: 2005- : Amsterdam : Elsevier Science
Original Publication: Amsterdam, North Holland Pub. Co.
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MeSH Terms:
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Angiotensin-Converting Enzyme 2*/antagonists & inhibitors
Angiotensin-Converting Enzyme 2*/metabolism
COVID-19*/metabolism
SARS-CoV-2*/drug effects
SARS-CoV-2*/physiology
COVID-19 Drug Treatment*
Doxepin/*pharmacology
Protein Binding/*drug effects
Virus Internalization/*drug effects
Antiviral Agents/pharmacology ; Drug Repositioning ; HEK293 Cells ; Histamine H1 Antagonists/classification ; Histamine H1 Antagonists/pharmacology ; Humans ; Spike Glycoprotein, Coronavirus/metabolism
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Contributed Indexing:
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Keywords: Angiotensin-converting enzyme 2; Doxepin; Drug repositioning; Histamine H(1) receptor antagonist; SARS-CoV-2
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Substance Nomenclature:
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0 (Antiviral Agents)
0 (Histamine H1 Antagonists)
0 (Spike Glycoprotein, Coronavirus)
1668-19-5 (Doxepin)
EC 3.4.17.23 (Angiotensin-Converting Enzyme 2)
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Entry Date(s):
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Date Created: 20210126 Date Completed: 20210311 Latest Revision: 20221207
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Update Code:
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20240105
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PubMed Central ID:
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PMC7826143
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DOI:
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10.1016/j.ejphar.2021.173897
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PMID:
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33497607
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The spread of the corona virus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been intensifying in the past year, posing a huge threat to global health. There is an urgent need for effective drugs and vaccines to fight the COVID-19, but their advent may not be quite fast. Drug repurposing is a feasible strategy in the current situation, which could greatly shorten drug development time and help to response quickly to the novel virus outbreak. It has been reported that histamine H 1 receptor antagonists have broad-spectrum antiviral effects. Therefore, in this study, we aim to screen potential drugs among histamine H 1 receptor antagonists that may inhibit SARS-CoV-2 infection. Based on the model of angiotensin-converting enzyme 2 (ACE2) overexpressing HEK293T cell membrane chromatography (CMC), five FDA-approved histamine H 1 receptor antagonists were found to have bioaffinity to ACE2. Then we determined the interaction between these drugs and ACE2 by frontal analysis and surface plasmon resonance (SPR), which consistently demonstrated that these hits bind to ACE2 at micromolar levels of affinity. Through the pseudovirus assay, we finally identified that doxepin could inhibit SARS-CoV-2 spike pseudovirus from entering the ACE2-expressing cell, reducing the infection rate to 25.82%. These preliminary results indicate that the histamine H 1 receptor antagonist, doxepin, is a viable drug candidate for clinical trials. Therefore, we hope the work timely provides rational help for developing anti-SARS-CoV-2 drugs to control the rapid spread of SARS-CoV-2.
(Copyright © 2021 Elsevier B.V. All rights reserved.)
