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

• Published in: Communications biology 2021-12, Vol.4 (1), p.1347-10
• Main Authors: Toft-Bertelsen, Trine Lisberg, Jeppesen, Mads Gravers, Tzortzini, Eva, Xue, Kai, Giller, Karin, Becker, Stefan, Mujezinovic, Amer, Bentzen, Bo Hjorth, B Andreas, Loren, Kolocouris, Antonios, Kledal, Thomas Nitschke, Rosenkilde, Mette Marie
• Format: Article
• Language: English
• Subjects: Amantadine - pharmacology; Amiloride - analogs & derivatives; Amiloride - pharmacology; Antiviral Agents - pharmacology; Ion Channels - physiology; Rimantadine - pharmacology; SARS-CoV-2 - drug effects; Viral Proteins - physiology
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-021-02866-9

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.