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Common cardiac medications potently inhibit ACE2 binding to the SARS-CoV-2 Spike, and block virus penetration and infectivity in human lung cells.
Caohuy, Hung; Eidelman, Ofer; Chen, Tinghua; Liu, Shufeng; Yang, Qingfeng; Bera, Alakesh; Walton, Nathan I; Wang, Tony T; Pollard, Harvey B.
  • 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.
  • Eidelman O; 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.
  • Liu S; Collaborative Health Initiative Research Program (CHIRP), Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, 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.
  • Bera A; Collaborative Health Initiative Research Program (CHIRP), Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.
  • Walton NI; 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.
Sci Rep ; 11(1): 22195, 2021 11 12.
Article in English | MEDLINE | ID: covidwho-1514424
ABSTRACT
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 ACE2Spike 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/ß/γ [D614G] S1 proteins. These drugs also inhibit ACE2 binding to the Original RBD, as well as to RBD proteins containing the ß [E484K], Mink [Y453F] and α/ß/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 ACE2RBD 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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Cardiotonic Agents / Virus Internalization / Spike Glycoprotein, Coronavirus / Angiotensin-Converting Enzyme 2 / SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: Sci Rep Year: 2021 Document Type: Article Affiliation country: S41598-021-01690-9

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Cardiotonic Agents / Virus Internalization / Spike Glycoprotein, Coronavirus / Angiotensin-Converting Enzyme 2 / SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: Sci Rep Year: 2021 Document Type: Article Affiliation country: S41598-021-01690-9