Amantadine inhibits known and novel ion channels encoded by SARS-CoV-2 in vitro
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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Amantadine inhibits known and novel ion channels encoded by SARS-CoV-2 in vitro. / Toft-Bertelsen, Trine Lisberg; Jeppesen, Mads Gravers; Tzortzini, Eva; Xue, Kai; Giller, Karin; Becker, Stefan; Mujezinovic, Amer; Bentzen, Bo Hjorth; Andreas, Loren B.; Kolocouris, Antonios; Kledal, Thomas Nitschke; Rosenkilde, Mette Marie.
I: Communications Biology, Bind 4, 1347, 2021.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Amantadine inhibits known and novel ion channels encoded by SARS-CoV-2 in vitro
AU - Toft-Bertelsen, Trine Lisberg
AU - Jeppesen, Mads Gravers
AU - Tzortzini, Eva
AU - Xue, Kai
AU - Giller, Karin
AU - Becker, Stefan
AU - Mujezinovic, Amer
AU - Bentzen, Bo Hjorth
AU - Andreas, Loren B.
AU - Kolocouris, Antonios
AU - Kledal, Thomas Nitschke
AU - Rosenkilde, Mette Marie
N1 - Author Correction: https://www.nature.com/articles/s42003-021-02940-2
PY - 2021
Y1 - 2021
N2 - 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
AB - 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
U2 - 10.1038/s42003-021-02866-9
DO - 10.1038/s42003-021-02866-9
M3 - Journal article
C2 - 34853399
VL - 4
JO - Communications Biology
JF - Communications Biology
SN - 2399-3642
M1 - 1347
ER -
ID: 286483773