Functional screenings for inhibitors of SARS-CoV-2 Spike protein-induced cellular syncytia identifies approved drugs for COVID-19 therapy

Post-mortem analysis of lungs from COVID-19 patients revealed the presence of numerous pneumocyte syncytia (cells that have fused with each other to form large multi-nuclear structures). Since the expression of the SARS-CoV-2 Spike protein in heterologous cells results in the formation of syncytia, this system was used to screen for FDA/EMA-approved drugs that inhibit Spike-mediated heterologous cell-cell fusion. Of the successful drugs isolated in the screen, three of them were studied further. All three, in addition to inhibiting syncytia formation, also inhibited viral replication. The top candidate was found to also be an inhibitor of a calcium-activated chloride channel that is involved in cell-cell fusion. In our lab at the Centre for Developmental Neurobiology, KCL, we used electrophysiology to show that cells expressing the SARS-CoV-2 Spike protein have an increased channel activity in line with the idea that the virus stimulates syncytia formation via its activation. Our data may also help explain some of the side-effects of COVID-19, which include alveolar oedema and diarrhoea, both of which could be potentially linked to the activity of this channel.