tetano
Editor, Senior Moderator
ACS Chem Neurosci
. 2021 Mar 31.
doi: 10.1021/acschemneuro.0c00619. Online ahead of print.
Novel Compounds Targeting Neuropilin Receptor 1 with Potential To Interfere with SARS-CoV-2 Virus Entry
Samantha Perez-Miller[SUP] 1 2 [/SUP], Marcel Patek[SUP] 3 [/SUP], Aubin Moutal[SUP] 1 [/SUP], Paz Duran[SUP] 1 [/SUP], Carly R Cabel[SUP] 4 5 [/SUP], Curtis A Thorne[SUP] 4 5 6 [/SUP], Samuel K Campos[SUP] 5 6 7 [/SUP], Rajesh Khanna[SUP] 1 2 8 [/SUP]
Affiliations
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 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.
Keywords: ELISA; Neuropilin-1; SARS-CoV-2; VEGF-A; VSV; cancer; natural compounds; pain; small molecules.
. 2021 Mar 31.
doi: 10.1021/acschemneuro.0c00619. Online ahead of print.
Novel Compounds Targeting Neuropilin Receptor 1 with Potential To Interfere with SARS-CoV-2 Virus Entry
Samantha Perez-Miller[SUP] 1 2 [/SUP], Marcel Patek[SUP] 3 [/SUP], Aubin Moutal[SUP] 1 [/SUP], Paz Duran[SUP] 1 [/SUP], Carly R Cabel[SUP] 4 5 [/SUP], Curtis A Thorne[SUP] 4 5 6 [/SUP], Samuel K Campos[SUP] 5 6 7 [/SUP], Rajesh Khanna[SUP] 1 2 8 [/SUP]
Affiliations
- PMID: 33787218
- DOI: 10.1021/acschemneuro.0c00619
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 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.
Keywords: ELISA; Neuropilin-1; SARS-CoV-2; VEGF-A; VSV; cancer; natural compounds; pain; small molecules.