Amantadine has potential for the treatment of COVID-19 because it inhibits known and novel ion channels encoded by SARS-CoV-2.

Autor: Toft-Bertelsen TL; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Jeppesen MG; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Synklino ApS, Charlottenlund, Denmark., Tzortzini E; Laboratory of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis-Zografou, Athens, Greece., Xue K; Department of NMR-based structural biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany., Giller K; Department of NMR-based structural biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany., Becker S; Department of NMR-based structural biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany., Mujezinovic A; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Bentzen BH; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., B Andreas L; Department of NMR-based structural biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany., Kolocouris A; Laboratory of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis-Zografou, Athens, Greece., Kledal TN; Synklino ApS, Charlottenlund, Denmark. tnk@synklino.com., Rosenkilde MM; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. rosenkilde@sund.ku.dk.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2021 Dec 01; Vol. 4 (1), pp. 1347. Date of Electronic Publication: 2021 Dec 01.
DOI: 10.1038/s42003-021-02866-9
Abstrakt: The dire need for COVID-19 treatments has inspired strategies of repurposing approved drugs. Amantadine has been suggested as a candidate, and cellular as well as clinical studies have indicated beneficial effects of this drug. We demonstrate that amantadine and hexamethylene-amiloride (HMA), but not rimantadine, block the ion channel activity of Protein E from SARS-CoV-2, a conserved viroporin among coronaviruses. These findings agree with their binding to Protein E as evaluated by solution NMR and molecular dynamics simulations. Moreover, we identify two novel viroporins of SARS-CoV-2; ORF7b and ORF10, by showing ion channel activity in a X. laevis oocyte expression system. Notably, amantadine also blocks the ion channel activity of ORF10, thereby providing two ion channel targets in SARS-CoV-2 for amantadine treatment in COVID-19 patients. A screen of known viroporin inhibitors on Protein E, ORF7b, ORF10 and Protein 3a from SARS-CoV-2 revealed inhibition of Protein E and ORF7b by emodin and xanthene, the latter also blocking Protein 3a. This illustrates a general potential of well-known ion channel blockers against SARS-CoV-2 and specifically a dual molecular basis for the promising effects of amantadine in COVID-19 treatment. We therefore propose amantadine as a novel, cheap, readily available and effective way to treat COVID-19.
(© 2021. The Author(s).)
Databáze: MEDLINE
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