How many SARS-CoV-2 “viroporins” are really ion channels?

Abstract

The SARS-CoV-2 virus uses a small number of viral proteins to enter host cells and disrupt their activity, including the spike (S), membrane (M), and envelope (E) proteins, as well as a number of accessory proteins of unknown function (Orf3a, Orf8, Orf10, etc.), some of which may function to alter ion flux across membranes. Toft-Bertelsen et al.1 recently reported that the drug amantadine may interact with virally encoded ion channels and proposed that inhibitors of these “viroporins” might have therapeutic use in COVID-19. We concur with the idea that the E protein of SARS-CoV-2 can form an ion channel and that amantadine inhibits this channel, but we suggest below that a number of additional specific criteria need to be met in order for SARS-CoV-2 accessory proteins (Orf3a, Orf8, Orf10) to be accepted as having ion channel activity, and that further work will be necessary. This field represents a neglected area of overlap between biophysics and virology that continues to be understudied and underfunded and clearly merits greater attention from the relevant funding agencies.