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Papers of the Week

Papers: 24 Dec 2022 - 30 Dec 2022

2022 Dec 28



Computational design of peptides to target Na1.7 channel with high potency and selectivity for the treatment of pain.


Nguyen PT, Nguyen HM, Wagner KM, Stewart R, Singh V, Thapa P, Chen Y-J, Lillya MW, Ton A T, Kondo R, Ghetti A, Pennington MW, Hammock B, Griffith TN, Sack JT, Wulff H, Yarov-Yarovoy V
Elife. 2022 Dec 28; 11.
PMID: 36576241.


The voltage-gated sodium Na1.7 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 Na1.7 activation. Here we used available structural and experimental data to guide Rosetta design of potent and selective ProTx-II-based peptide inhibitors of human Na1.7 channels. Functional testing of designed peptides using electrophysiology identified the PTx2-3127 and PTx2-3258 peptides with ICs of 7 nM and 4 nM for hNa1.7 and more than 1,000-fold selectivity over human Na1.1, Na1.3, Na1.4, Na1.5, Na1.8, and Na1.9 channels. PTx2-3127 inhibits Na1.7 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 Na1.7 channels have transformative potential to define a new class of biologics to treat pain.