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Tytuł pozycji:

Common cardiac medications potently inhibit ACE2 binding to the SARS-CoV-2 Spike, and block virus penetration and infectivity in human lung cells.

Tytuł:
Common cardiac medications potently inhibit ACE2 binding to the SARS-CoV-2 Spike, and block virus penetration and infectivity in human lung cells.
Autorzy:
Caohuy H; Department of Anatomy, Physiology and Genetics, Uniformed Services University School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.; Collaborative Health Initiative Research Program (CHIRP), Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.
Eidelman O; Department of Anatomy, Physiology and Genetics, Uniformed Services University School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.; Collaborative Health Initiative Research Program (CHIRP), Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.
Chen T; Department of Anatomy, Physiology and Genetics, Uniformed Services University School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.; Collaborative Health Initiative Research Program (CHIRP), Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.; Consortium for Health and Military Performance (CHAMP), Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.
Liu S; Laboratory of Vector-Borne Viral Diseases, Division of Viral Products, Center for Biologics Evaluation (CBER), U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA.
Yang Q; Department of Anatomy, Physiology and Genetics, Uniformed Services University School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.; Center for the Study of Traumatic Stress (CSTS), Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.
Bera A; Department of Anatomy, Physiology and Genetics, Uniformed Services University School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.; Collaborative Health Initiative Research Program (CHIRP), Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.
Walton NI; Department of Anatomy, Physiology and Genetics, Uniformed Services University School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.; Collaborative Health Initiative Research Program (CHIRP), Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.; Consortium for Health and Military Performance (CHAMP), Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.
Wang TT; Laboratory of Vector-Borne Viral Diseases, Division of Viral Products, Center for Biologics Evaluation (CBER), U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA.
Pollard HB; Department of Anatomy, Physiology and Genetics, Uniformed Services University School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA. .; Collaborative Health Initiative Research Program (CHIRP), Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA. .; Consortium for Health and Military Performance (CHAMP), Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA. .
Źródło:
Scientific reports [Sci Rep] 2021 Nov 12; Vol. 11 (1), pp. 22195. Date of Electronic Publication: 2021 Nov 12.
Typ publikacji:
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
Język:
English
Imprint Name(s):
Original Publication: London : Nature Publishing Group, copyright 2011-
MeSH Terms:
COVID-19 Drug Treatment*
Angiotensin-Converting Enzyme 2/*metabolism
Cardiotonic Agents/*pharmacology
SARS-CoV-2/*drug effects
Spike Glycoprotein, Coronavirus/*metabolism
Virus Internalization/*drug effects
A549 Cells ; Animals ; COVID-19/metabolism ; Chlorocebus aethiops ; Digitoxin/pharmacology ; Digoxin/pharmacology ; Humans ; Lung/drug effects ; Lung/metabolism ; Ouabain/pharmacology ; Protein Binding/drug effects ; SARS-CoV-2/physiology ; Vero Cells
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Substance Nomenclature:
0 (Cardiotonic Agents)
0 (Spike Glycoprotein, Coronavirus)
0 (spike protein, SARS-CoV-2)
5ACL011P69 (Ouabain)
73K4184T59 (Digoxin)
E90NZP2L9U (Digitoxin)
EC 3.4.17.23 (ACE2 protein, human)
EC 3.4.17.23 (Angiotensin-Converting Enzyme 2)
Entry Date(s):
Date Created: 20211113 Date Completed: 20211125 Latest Revision: 20221207
Update Code:
20240104
PubMed Central ID:
PMC8589851
DOI:
10.1038/s41598-021-01690-9
PMID:
34773067
Czasopismo naukowe
To initiate SARS-CoV-2 infection, the Receptor Binding Domain (RBD) on the viral spike protein must first bind to the host receptor ACE2 protein on pulmonary and other ACE2-expressing cells. We hypothesized that cardiac glycoside drugs might block the binding reaction between ACE2 and the Spike (S) protein, and thus block viral penetration into target cells. To test this hypothesis we developed a biochemical assay for ACE2:Spike binding, and tested cardiac glycosides as inhibitors of binding. Here we report that ouabain, digitoxin, and digoxin, as well as sugar-free derivatives digitoxigenin and digoxigenin, are high-affinity competitive inhibitors of ACE2 binding to the Original [D614] S1 and the α/β/γ [D614G] S1 proteins. These drugs also inhibit ACE2 binding to the Original RBD, as well as to RBD proteins containing the β [E484K], Mink [Y453F] and α/β/γ [N501Y] mutations. As hypothesized, we also found that ouabain, digitoxin and digoxin blocked penetration by SARS-CoV-2 Spike-pseudotyped virus into human lung cells, and infectivity by native SARS-CoV-2. These data indicate that cardiac glycosides may block viral penetration into the target cell by first inhibiting ACE2:RBD binding. Clinical concentrations of ouabain and digitoxin are relatively safe for short term use for subjects with normal hearts. It has therefore not escaped our attention that these common cardiac medications could be deployed worldwide as inexpensive repurposed drugs for anti-COVID-19 therapy.
(© 2021. The Author(s).)

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