Computational design of peptides to target NaV1.7 channel with high potency and selectivity for the treatment of pain

  1. Phuong T Nguyen
  2. Hai M Nguyen
  3. Karen M Wagner
  4. Robert Stewart
  5. Vikrant Singh
  6. Parashar Thapa
  7. Yi-Je Chen
  8. Mark W Lillya
  9. Anh Tuan Ton
  10. Richard Kondo
  11. Andre Ghetti
  12. Michael W Pennington
  13. Bruce Hammock
  14. Theanne N Griffith
  15. Jon T Sack
  16. Heike Wulff  Is a corresponding author
  17. Vladimir Yarov-Yarovoy  Is a corresponding author
  1. University of California, Davis, United States
  2. University of California Davis Medical Center, United States
  3. AnaBios, United States
  4. 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

  1. Phuong T Nguyen

    Department of Physiology and Membrane Biology, University of California, Davis, Davis, United States
    Competing interests
    Phuong T Nguyen, is named inventor on a patent application entitled 'Peptides targeting sodium channels to treat pain' based on this research, filed by the University of California.(U.S. provisionalapplication no. 63/358,684, filed July 6, 2022)..
  2. Hai M Nguyen

    Department of Pharmacology, University of California, Davis, Davis, United States
    Competing interests
    Hai M Nguyen, is named inventor on a patent application entitled 'Peptides targeting sodium channels to treat pain' based on this research, filed by the University of California. (U.S. provisionalapplication no. 63/358,684, filed July 6, 2022)..
  3. Karen M Wagner

    Department of Entomology and Nematology, University of California, Davis, Davis, United States
    Competing interests
    Karen M Wagner, is named inventor on a patent application entitled 'Peptides targeting sodium channels to treat pain' based on this research, filed by the University of California. (U.S. provisionalapplication no. 63/358,684, filed July 6, 2022)..
  4. Robert Stewart

    Department of Physiology and Membrane Biology, University of California, Davis, Davis, United States
    Competing interests
    No competing interests declared.
  5. Vikrant Singh

    Department of Pharmacology, University of California, Davis, Davis, United States
    Competing interests
    No competing interests declared.
  6. Parashar Thapa

    Department of Physiology and Membrane Biology, University of California, Davis, Davis, United States
    Competing interests
    No competing interests declared.
  7. Yi-Je Chen

    Department of Pharmacology, University of California, Davis, Davis, United States
    Competing interests
    No competing interests declared.
  8. Mark W Lillya

    Department of Physiology and Membrane Biology, University of California Davis Medical Center, Davis, United States
    Competing interests
    No competing interests declared.
  9. Anh Tuan Ton

    AnaBios, San Diego, United States
    Competing interests
    Anh Tuan Ton, is affiliated with AnaBios Corporation. The author has no financial interests to declare..
  10. Richard Kondo

    AnaBios, San Diego, United States
    Competing interests
    Richard Kondo, is affiliated with AnaBios Corporation. The author has no financial interests to declare..
  11. Andre Ghetti

    AnaBios, San Diego, United States
    Competing interests
    Andre Ghetti, is affiliated with AnaBios Corporation. The author has no financial interests to declare..
  12. Michael W Pennington

    AmbioPharm Inc, North Augusta, United States
    Competing interests
    Michael W Pennington, is affiliated with Ambiopharm Inc. The author has no financial interests to declare..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5446-3447
  13. Bruce Hammock

    Department of Entomology and Nematology, University of California, Davis, Davis, United States
    Competing interests
    Bruce Hammock, is named inventor on a patent application entitled 'Peptides targeting sodium channels to treat pain' based on this research, filed by the University of California. (U.S. provisionalapplication no. 63/358,684, filed July 6, 2022)..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1408-8317
  14. Theanne N Griffith

    Department of Physiology and Membrane Biology, University of California, Davis, Davis, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0090-6286
  15. Jon T Sack

    Department of Physiology and Membrane Biology, University of California, Davis, Davis, United States
    Competing interests
    Jon T Sack, Reviewing editor, eLife.Is named inventor on a patent application entitled 'Peptides targeting sodium channels to treat pain' based on this research, filed by the application no. 63/358,684, filed July 6, 2022)..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6975-982X
  16. Heike Wulff

    Department of Pharmacology, University of California, Davis, Davis, United States
    For correspondence
    hwulff@ucdavis.edu
    Competing interests
    Heike Wulff, is named inventor on a patent application entitled 'Peptides targeting sodium channels to treat pain' based on this research, filed by the University of California. (U.S. provisionalapplication no. 63/358,684, filed July 6, 2022)..
  17. Vladimir Yarov-Yarovoy

    Department of Physiology and Membrane Biology, University of California, Davis, Davis, United States
    For correspondence
    yarovoy@ucdavis.edu
    Competing interests
    Vladimir Yarov-Yarovoy, is named inventor on a patent application entitled 'Peptides targeting sodium channels to treat pain' based on this research, filed by the University of California. (U.S. provisionalapplication no. 63/358,684, filed July 6, 2022)..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2325-4834

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

  1. 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

  1. Received: July 9, 2022
  2. Preprint posted: July 22, 2022 (view preprint)
  3. Accepted: December 23, 2022
  4. Accepted Manuscript published: December 28, 2022 (version 1)
  5. Version of Record published: January 10, 2023 (version 2)
  6. 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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  1. Phuong T Nguyen
  2. Hai M Nguyen
  3. Karen M Wagner
  4. Robert Stewart
  5. Vikrant Singh
  6. Parashar Thapa
  7. Yi-Je Chen
  8. Mark W Lillya
  9. Anh Tuan Ton
  10. Richard Kondo
  11. Andre Ghetti
  12. Michael W Pennington
  13. Bruce Hammock
  14. Theanne N Griffith
  15. Jon T Sack
  16. Heike Wulff
  17. Vladimir Yarov-Yarovoy
(2022)
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

Share this article

https://doi.org/10.7554/eLife.81727

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