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Commun Biol
. 2021 Dec 1;4(1):1347.
doi: 10.1038/s42003-021-02866-9.
Amantadine has potential for the treatment of COVID-19 because it inhibits known and novel ion channels encoded by SARS-CoV-2
Trine Lisberg Toft-Bertelsen # 1 2 , Mads Gravers Jeppesen # 1 3 , Eva Tzortzini 4 , Kai Xue 5 , Karin Giller 5 , Stefan Becker 5 , Amer Mujezinovic 1 , Bo Hjorth Bentzen 1 , Loren B Andreas 5 , Antonios Kolocouris 4 , Thomas Nitschke Kledal 6 , Mette Marie Rosenkilde 7
Affiliations
- PMID: 34853399
- DOI: 10.1038/s42003-021-02866-9
Abstract
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.