Neuropilins (NRPs) are transmembrane glycoproteins that lack direct signaling functions and therefore participate as co-receptors in various physiological and pathological processes, including the recent COVID-19 pandemic. NRPs were found to provide an additional entry point for SARS-CoV-2 by spike protein binding to the well-known and explored binding pocket on the b1 domain of NRP1, which allows the virus to enter host cells and significantly increases its infectivity. Therefore, the b1 subunit has been identified as a target for the development of small molecule inhibitors that could interfere with the binding of the virus and prevent its entry. With the aim to identify such inhibitors, we performed an extensive virtual screening of a large library of small molecules with drug-like properties. The compounds with the highest scoring binding modes in the b1 binding pocket were further biologically evaluated for blockade of SARS-CoV-2 spike binding to NRP1. Two of these compounds with completely new scaffolds showed stronger inhibition than the EG00229 control, a known NRP1 inhibitor that was also shown to block spike protein binding to NRP1. Since the COVID-19 pandemic is far from over, these compounds exhibit a great potential for the further development of small molecule inhibitors of SARS-CoV-2 to attenuate viral infectivity and prevent associated diseases as well as for the development of novel protein-protein inhibitors in general.

Novel small-molecule inhibitors of the SARS-CoV-2 spike protein binding to neuropilin 1

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