coronavirus fusion inhibitors identified by high content screening
2The Wohl Drug Discovery Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Israel
The fight against the Covid-19 pandemic is ongoing worldwide, emphasizing the need for antiviral drugs that block emerging coronaviruses (CoVs). A critical stage during infection is fusion of the viral envelope with the host-cell membrane, which depends on the conserved S2 domain of the viral Spike (S) protein. Hence, targeting the S2 domain is a promising approach to achieve pan-CoV inhibition. Since MERS- and SARS- S proteins bind to different cell-surface receptors through the rapidly diversifying S1 domain, we reasoned that compounds that inhibit both must target the S2 domain. We performed a high-throughput screen of 173,227 unique compounds and classified them based on their ability to inhibit infection of pseudoviruses bearing either MERS or SARS-2 S proteins. This analysis identified PCM-000238 as a potent pan-coronavirus inhibitor at sub-micromolar concentrations, paving the way to in vivo and clinical studies.