Computational design of peptides to target NaV1.7 channel with high potency and selectivity for the treatment of pain
- University of California, Davis, United States
- University of California Davis Medical Center, United States
- AnaBios, United States
- AmbioPharm Inc, United States
Abstract
The voltage-gated sodium NaV1.7 channel plays a key role as a mediator of action potential propagation in C-fiber nociceptors and is an established molecular target for pain therapy. ProTx-II is a potent and moderately selective peptide toxin from tarantula venom that inhibits human NaV1.7 activation. Here we used available structural and experimental data to guide Rosetta design of potent and selective ProTx-II-based peptide inhibitors of human NaV1.7 channels. Functional testing of designed peptides using electrophysiology identified the PTx2-3127 and PTx2-3258 peptides with IC50s of 7 nM and 4 nM for hNaV1.7 and more than 1,000-fold selectivity over human NaV1.1, NaV1.3, NaV1.4, NaV1.5, NaV1.8, and NaV1.9 channels. PTx2-3127 inhibits NaV1.7 currents in mouse and human sensory neurons and shows efficacy in rat models of chronic and thermal pain when administered intrathecally. Rationally-designed peptide inhibitors of human NaV1.7 channels have transformative potential to define a new class of biologics to treat pain.
Data availability
All data generated or analysed during this study are included in the manuscript.
Article and author information
Author details
Michael W Pennington
Theanne N Griffith
Vladimir Yarov-Yarovoy
Funding
National Institute of Neurological Disorders and Stroke (UG3NS114956)
- Phuong T Nguyen
- Hai M Nguyen
- Karen M Wagner
- Robert Stewart
- Vikrant Singh
- Parashar Thapa
- Yi-Je Chen
- Mark W Lillya
- Anh Tuan Ton
- Richard Kondo
- Andre Ghetti
- Michael W Pennington
- Bruce Hammock
- Theanne N Griffith
- Jon T Sack
- Heike Wulff
- Vladimir Yarov-Yarovoy
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Leon D Islas, Universidad Nacional Autónoma de México, Mexico
Ethics
Animal experimentation: Research involving vertebrate animals was done at the University of California following protocols reviewed and approved by the UC Davis Institutional Animal Care and Use Committee (UCD IACUC) - Animal Welfare Assurance Number A3433-01. The animals were cared for by the Center for Laboratory Animal Science (CLAS) Veterinary Services under a currently AAALAC approved program under the direction of Dr. Laura Brignolo (Campus Veterinarian). The animals were housed in NIH-approved facilities in CLAS and are observed daily by technicians. Unusual events are reported to the on call veterinarian, as well as to the investigator according to posted protocols. Other maintenance veterinary care was conducted according to NIH guidelines on the Use and Care of Animals. Facilities were inspected regularly according to NIH and AAALAC guidelines.
Version history
- Received: July 9, 2022
- Preprint posted: July 22, 2022 (view preprint)
- Accepted: December 23, 2022
- Accepted Manuscript published: December 28, 2022 (version 1)
- Version of Record published: January 10, 2023 (version 2)
- Version of Record updated: February 17, 2023 (version 3)
Copyright
© 2022, Nguyen et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Computational design of peptides to target NaV1.7 channel with high potency and selectivity for the treatment of pain
eLife 11:e81727.
https://doi.org/10.7554/eLife.81727
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