Oct 1, 2020Paper

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

BioRxiv : the Preprint Server for Biology
Samantha Perez-MillerRajesh Khanna

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 val...Continue Reading

Citations

Dec 10, 2020·Immunity & Ageing : I & a·Alistair V W NunnJimmy D Bell
Apr 6, 2021·Computational and Structural Biotechnology Journal·Amie Jobe, Ranjit Vijayan
Jan 14, 2021·Molecular Neurobiology·Mohan Kumar Muthu KaruppanMadepalli K Lakshmana
Jul 3, 2021·Journal of Clinical Medicine·Monika Gudowska-Sawczuk, Barbara Mroczko

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