# Mechanism of dual Nav1.7 and Nav1.8 block by a NaV inhibitory peptide

> **NIH NIH R21** · MEDICAL COLLEGE OF WISCONSIN · 2024 · $249,250

## Abstract

Mechanism of dual NaV1.7 and NaV1.8 block by a NaV inhibitory peptide aptamer
Summary/Abstract: Multiple sensory neuronal sodium channels (NaVs) contribute to pain pathogenesis,
indicating that development of a strategy for specific block of multiple NaVs in the pathological sensory neurons
would be more effective for inhibiting pain signals than inhibiting only single NaV subtype. We discovered a
polyacidic peptide from NaV1.7 intracellular segment and voltage-clamp recording shows that this peptide
potently inhibits sodium currents conducted by both NaV1.7 and NaV1.8 (NaV1.7/1.8) channels. This dual
NaV1.7/1.8 inhibitory peptide aptamer (named 1.7/1.8iPA, 38mer) contains a conserved Ankyrin (AnkG) binding
domain and a multi-PDZ-domain protein
class I binding domain (Pdzd2-I) between NaV1.7 and NaV1.8,
suggesting that either AnkG or Pdzd2-I domain or both within 1.7/1.8iPA may contribute to its dual NaV1.7/1.8
inhibition. The overall goal of this proposal is to investigate 1) whether AnkG and/or Pdzd2-I domains in
1.7/1.8iPA is responsible for its dual NaV1.7/1.8 inhibition, and 2) whether expression of sequence defined
1.7/1.8iPA in the primary sensory neurons (PSN) will suppress PSN excitability, supporting 1.7/1.8iPA as a
potential analgesic lead. Two specific aims will be investigated to test the hypothesis that
1.7/1.8iPA elicits
dual
block of NaV1.7/1.8 currents via a combined effects of AnkG and Pdzd2-I domains, leading to suppression of
PSN action potential firing. Specific aim 1 will investigate and determine
ion channel selectivity of 1.7/1.8iPA by
in vitro of cell-based voltage-clamp recordings using HEK cells stably expressing various NaV subtypes and
NG108-15 neuronal cells that naturally express potassium channels KV7.2/7.3 (both containing conserved AnkG
binding domain). Specific aim 2 will
determine electrogenesis and biological activity (neurotoxicity and animal
behaviors) of 1.7/1.8iPA expression in the rat PSNs. Successful completion of this application will provide
sufficient data
to determine whether 1.7/1.8iPA is a potential analgesic lead to be further developed for AAV-
mediated, PSN-specific dual NaV1.7/1.8 inhibition to treat chronic pain.

## Key facts

- **NIH application ID:** 10869190
- **Project number:** 1R21NS137014-01
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Hongwei Yu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $249,250
- **Award type:** 1
- **Project period:** 2024-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10869190

## Citation

> US National Institutes of Health, RePORTER application 10869190, Mechanism of dual Nav1.7 and Nav1.8 block by a NaV inhibitory peptide (1R21NS137014-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10869190. Licensed CC0.

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