Novel Small-Molecule Inhibitors of the SARS-CoV-2 Spike Protein Binding to Neuropilin 1

Anja Kolarič; Marko Jukič; Urban Bren

doi:10.3390/ph15020165

Novel Small-Molecule Inhibitors of the SARS-CoV-2 Spike Protein Binding to Neuropilin 1

Pharmaceuticals (Basel). 2022 Jan 28;15(2):165. doi: 10.3390/ph15020165.

Authors

Anja Kolarič¹, Marko Jukič^{1

2}, Urban Bren^{1

2}

Affiliations

¹ Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova 17, SI-2000 Maribor, Slovenia.
² Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska, Glagoljaška 8, SI-6000 Koper, Slovenia.

Abstract

Furin cleavage of the SARS-CoV-2 spike protein results in a polybasic terminal sequence termed the C-end rule (CendR), which is responsible for the binding to neuropilin 1 (NRP1), enhancing viral infectivity and entry into the cell. Here we report the identification of 20 small-molecule inhibitors that emerged from a virtual screening of nearly 950,000 drug-like compounds that bind with high probability to the CendR-binding pocket of NRP1. In a spike NRP1 binding assay, two of these compounds displayed a stronger inhibition of spike protein binding to NRP1 than the known NRP1 antagonist EG00229, for which the inhibition of the CendR peptide binding to NRP1 was also experimentally confirmed. These compounds present a good starting point for the design of small-molecule antagonists against the SARS-CoV-2 viral entry.

Keywords: COVID-19; SARS-CoV-2; in vitro binding assay; molecular docking; neuropilin 1; small-molecule antagonists; spike binding inhibitors; virtual screening.

Abstract

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