# Design of de novo peptides and electrophysiological testing for voltage-gated sodium channel 1.7 inhibition related to chronic pain treatment

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $37,185

## Abstract

Project Summary/Abstract
Current drug discovery efforts for non-addictive, chronic pain management are targeting human voltage-gated
sodium (hNaV) channels: pore-forming transmembrane proteins that evoke the fast action potential in excitable
neuronal, cardiac, and skeletal cells. Genetic and preclinical target validation studies have identified hNaV1.7,
hNaV1.8, hNaV1.9 channel subtypes as key proteins in pain signaling with emphasis on hNaV1.7 for its
predominant expression in the peripheral nervous system. Attempts at selectively targeting hNaV1.7 with pre-
clinical small-molecule drugs fall short due to non-selective binding to other hNaV channel subtypes and other
ion channel families; non-selective binding can lead to cardiac arrest, paralysis and seizure. Peptide toxins
originating from tarantula, spider, and scorpion have been identified as potent hNaV-inhibiting biologics.
Notably, Protoxin-II, the neurotoxin from the Peruvian green velvet tarantula, has approximately 1 nM half-
maximal inhibitory concentration (IC50) to hNav1.7. However, these peptide toxins also have non-selective
binding to hNav1.7. With recent cryo-EM structural images of Protoxin-II bound to voltage-sensing domain II of
hNaV1.7, it is now possible to design peptides mimicking Protoxin-II that are selective to hNaV1.7. Advances in
de novo protein design methods using Rosetta – a protein structure prediction and design software suite –
enable a new avenue of drug design and virtual screening prior to experimental validation. Thus, the project
aims to create new peptides inspired from Protoxin-II to selectively target hNaV1.7. The methodology designs
new peptide topologies that incorporate the Protoxin-II motif structurally shown to bind to hNaV1.7. The
peptides are further optimized to bind to residues unique to hNaV1.7: residues that are not targeted by natural
peptide toxins. Upon synthesis of candidate peptides, they will be validated to selectively target hNaV1.7 using
whole-cell patch-clamp electrophysiology. The results will improve our mechanistic understanding needed for
selective, yet potent hNaV1.7 inhibition. Further, this research will be the first attempt at using a combination of
Rosetta de novo protein design methods to create unique peptides selective for hNaV1.7. The applicant upon
completion of this project will have a refined expertise of computational protein design methods and receive
training in electrophysiology for the first time. Throughout this project, the sponsor and co-sponsor will
implement a training plan to strengthen the applicant’s knowledge of neuroscience and drug discovery, while
broadening their collaborative network, and sharpening their scientific communication skills. This plan is
tailored such that the applicant is prepared for an academic career designing peptide biologics for the
treatment and investigation of ion channel pathologies.

## Key facts

- **NIH application ID:** 10766833
- **Project number:** 5F31NS124337-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Brandon John Harris
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $37,185
- **Award type:** 5
- **Project period:** 2022-02-03 → 2024-12-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10766833

## Citation

> US National Institutes of Health, RePORTER application 10766833, Design of de novo peptides and electrophysiological testing for voltage-gated sodium channel 1.7 inhibition related to chronic pain treatment (5F31NS124337-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10766833. Licensed CC0.

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