SARS-CoV-2 comprehensive receptor profiling: mechanistic insight to drive new therapeutic strategies

Here we describe a hypothesis free approach to screen for interactions of SARS-CoV-2 spike (S) protein with human cell surface receptors. We used a library screening approach to detect binding interactions across one of the largest known panels of membrane-bound and soluble receptors, comprising 5845 targets, expressed recombinantly in human cells. We were able confirm and replicate SARS-CoV-2 binding to ACE2 and other putative coreceptors such as CD209 and CLEC4M. More significantly, we identified interactions with a number of novel SARS-CoV-2 S binding proteins. Three of these novel receptors, NID1, CNTN1 and APOA4 were specific to SARS-CoV-2, and not SARS-COV, with APOA4 binding the S-protein with equal affinity as ACE2. With this knowledge we may further understand the disease pathogenesis of COVID-19 patients and how infection by SARS-CoV-2 may lead to differences in pathology in specific organs or indeed the virulence observed in different ethnicities. Importantly we illustrate a methodology which can be used for rapid, unbiassed identification of cell surface receptors, to support drug screening and drug repurposing approaches for this and future pandemics.