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Amantadine has potential for the treatment of COVID-19 because it inhibits known and novel ion channels encoded by SARS-CoV-2.
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.
  • Toft-Bertelsen TL; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Jeppesen MG; Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Tzortzini E; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Xue K; Synklino ApS, Charlottenlund, Denmark.
  • Giller K; Laboratory of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis-Zografou, Athens, Greece.
  • Becker S; Department of NMR-based structural biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
  • Mujezinovic A; Department of NMR-based structural biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
  • Bentzen BH; Department of NMR-based structural biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
  • B Andreas L; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Kolocouris A; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Kledal TN; Department of NMR-based structural biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
  • Rosenkilde MM; Laboratory of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis-Zografou, Athens, Greece.
Commun Biol ; 4(1): 1347, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1852515
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Viral Proteins / Rimantadine / Amantadine / Amiloride / SARS-CoV-2 Type of study: Experimental Studies / Prognostic study Language: English Journal: Commun Biol Year: 2021 Document Type: Article Affiliation country: S42003-021-02866-9

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Viral Proteins / Rimantadine / Amantadine / Amiloride / SARS-CoV-2 Type of study: Experimental Studies / Prognostic study Language: English Journal: Commun Biol Year: 2021 Document Type: Article Affiliation country: S42003-021-02866-9