# Targeting the neuropilin-1 receptor (NRP-1)/VEGF-A axis for neuropathic pain

> **NIH NIH R41** · REGULONIX, LLC · 2021 · $419,470

## Abstract

ABSTRACT Revisions noted in blue font
First reported in December of 2019, coronavirus disease (COVID-19) has taken the world by storm, exacting a
heavy toll not only in terms of the number of deaths (~1,700,000) it has caused worldwide but also its decimation
of world economies (~$8.8 trillion). Because infection with SARS-CoV-2, the causative agent of COVD-19, can
be spread by asymptomatic, presymptomatic, and symptomatic carriers, the virus has been difficult to contain.
Our preliminary data shows that Spike protein, the major surface antigen of SARS-CoV-2, is analgesic.
Therefore, an explanation for the unabated spread (~77 million infected worldwide as of December 21, 2020)
may be that asymptomatic or presymptomatic individuals do not experience the pain and discomfort that act as
early warning signs of infection. We found that Spike protein binds to a surface receptor called neuropilin 1 (NRP-
1) to allow viral entry into cells. Vascular endothelial growth factor-A (VEGF-A) – a pro-nociceptive and
angiogenic factor, binds NRP-1, and induces mechanical allodynia and thermal hyperalgesia that is blocked by
Spike protein. Pharmacological antagonism of NRP-1 also blocks VEGF-A–induced pain behaviors. These
results identify NRP-1 as a new player in pain. How VEGF-A–activated signaling via NRP-1 leads to pain is an
open question. Leveraging this atypical pain-relieving function of the SARS-CoV-2 Spike interaction with NRP-
1, the laboratory of Dr. Rajesh Khanna (University of Arizona (UA)) performed a virtual screen of nearly 0.5
million compounds (diverse small molecules and commercially available natural products) against the VEGF-A
binding site on the NRP-1 b1 domain. Several of the top 20 ‘hit’ compounds from this screen have been validated
in in vitro and in vivo experiments, providing experimental proof of our in-silico predictions. We have partnered
with Regulonix LLC to test the hypothesis that SARS-CoV-2 Spike protein binding to NRP-1 triggers increases
in sodium and calcium channel activity to increase nociceptor activity culminating in enhanced pain and that this
signaling cascade can be blocked by inhibitors of NRP-1-VEGF-A interaction. Regulonix’s Specific Aims,
guided by quantitative goals, are: (1) to profile NRP-1 targeting compounds for their (i) to ability to bind to NRP-
1; (ii) to block the NRP-1-VEGF-A interaction using ELISA; and (iii) to inhibit VEGF-A mediated increase in
phosphorylation of VEGFR2, a proxy for activation of VEGF-A/NRP-1 signaling. A subset of compounds will be
tested for their ability to inhibit calcium and sodium currents in sensory neurons using whole-cell
electrophysiology with a smaller subset being tested in human DRGs to enhance rigor and the translational utility
of these compounds; (2) Profile NRP-1 targeting compounds for their in vitro cellular cytotoxicity, physico-
chemical, early ADME, and PK properties, and for off-target effects on GPCRs, kinases, ion channels and
alternative known pain targe...

## Key facts

- **NIH application ID:** 10321851
- **Project number:** 1R41NS122545-01A1
- **Recipient organization:** REGULONIX, LLC
- **Principal Investigator:** Rajesh Khanna
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $419,470
- **Award type:** 1
- **Project period:** 2021-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10321851

## Citation

> US National Institutes of Health, RePORTER application 10321851, Targeting the neuropilin-1 receptor (NRP-1)/VEGF-A axis for neuropathic pain (1R41NS122545-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10321851. Licensed CC0.

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