Τίτλος:
Amantadine has potential for the treatment of COVID-19 because it
inhibits known and novel ion channels encoded by SARS-CoV-2
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Toft-Bertelsen et al. describe repurposing of anti-influenza drug
amantadine and its derivatives for the treatment of SARS-CoV-2. They
show that Amantadine, Emodin and Xanthene show significant blockage of
ionchannels formed by SARS-CoV-2 which are crucial for its assembly and
pathophysiology.
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.
Συγγραφείς:
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
Περιοδικό:
Communicative & Integrative Biology
Εκδότης:
NATURE PORTFOLIO
DOI:
10.1038/s42003-021-02866-9
