In silico identification and validation of inhibitors of the interaction between neuropilin receptor 1 and SARS-CoV-2 Spike protein

Abstract Neuropilin-1 (NRP-1) is a multifunctional transmembrane receptor for ligands that affect developmental axonal growth and angiogenesis. In addition to a role in cancer, NRP-1 is a reported entry point for several viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)...

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Published in:	bioRxiv 2020-09
Main Authors:	Perez-Miller, Samantha, Patek, Marcel, Aubin Moutal, Cabel, Carly R, Thorne, Curtis A, Campos, Samuel K, Khanna, Rajesh
Format:	Article
Language:	eng
Subjects:	ACE2 Angiogenesis Angiotensin Angiotensin-converting enzyme 2 Arginine Binding sites Blood-brain barrier Cancer Central nervous system Coronaviridae Coronaviruses COVID-19 Enzyme-linked immunosorbent assay Enzymes Firing pattern Furin Natural products Neuropathy Neuropilin Opioids Pain Peptidyl-dipeptidase A Phosphorylation Physicochemical properties Proteins Severe acute respiratory syndrome coronavirus 2 Signal transduction Spike protein Stomatitis Vascular endothelial growth factor Viruses
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Summary:	Abstract Neuropilin-1 (NRP-1) is a multifunctional transmembrane receptor for ligands that affect developmental axonal growth and angiogenesis. In addition to a role in cancer, NRP-1 is a reported entry point for several viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19). The furin cleavage product of SARS-CoV-2 Spike protein takes advantage of the vascular endothelial growth factor A (VEGF-A) binding site on NRP-1 which accommodates a polybasic stretch ending in a C-terminal arginine. This site has long been a focus of drug discovery efforts for cancer therapeutics. We recently showed that interruption of the VEGF-A/NRP-1 signaling pathway ameliorates neuropathic pain and hypothesize that interference of this pathway by SARS-CoV-2 spike protein interferes with pain signaling. Here, we report hits from a small molecule and natural product screen of nearly 0.5 million compounds targeting the VEGF-A binding site on NRP-1. We identified nine chemical series with lead- or drug-like physico-chemical properties. Using an ELISA, we demonstrate that six compounds disrupt VEGF-A-NRP-1 binding more effectively than EG00229, a known NRP-1 inhibitor. Secondary validation in cells revealed that almost all tested compounds inhibited VEGF-A triggered VEGFR2 phosphorylation. Two compounds displayed robust inhibition of a recombinant vesicular stomatitis virus protein that utilizes the SARS-CoV-2 Spike for entry and fusion. These compounds represent a first step in a renewed effort to develop small molecule inhibitors of the VEGF-A/NRP-1 signaling for the treatment of neuropathic pain and cancer with the added potential of inhibiting SARS-CoV-2 virus entry. Competing Interest Statement R. Khanna is the co-founder of Regulonix LLC, a company developing non-opioids drugs for chronic pain. In addition, R. Khanna has patents US10287334 and US10441586 issued to Regulonix LLC. The other authors declare no competing financial interests. * Abbreviations ACE-2 angiotensin converting enzyme-2 ADME absorption, distribution, metabolism, and excretion BBB blood brain barrier CNS central nervous system COCONUT COlleCtion of Open NatUral producTs COVID-19 coronavirus disease 2019 ELISA enzyme linked immunosorbent assay NC natural compound NRP-1 Neuropilin 1 PDB protein data bank Ro5 Lipinski rule of 5 SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 VEGF-A vascular endothelial growth factor-A