posted on 2021-04-01, 10:29authored bySamantha Perez-Miller, Marcel Patek, Aubin Moutal, Paz Duran, Carly R. Cabel, Curtis A. Thorne, Samuel K. Campos, Rajesh Khanna
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 confirmed 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 physicochemical properties. Using 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 all tested compounds inhibited VEGF-A triggered VEGFR2
phosphorylation. Further, 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.