Computational design of peptides to target Na V 1.7 channel with high potency and selectivity for the treatment of pain.

The voltage-gated sodium Na V 1.7 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 Na V 1.7 activation. Here we used available structural and experimental data to guide Rosetta design of potent and selective ProTx-II-based peptide inhibitors of human Na V 1.7 channels. Functional testing of designed peptides using electrophysiology identified the PTx2-3127 and PTx2-3258 peptides with IC 50 s of 7 nM and 4 nM for hNa V 1.7 and more than 1,000-fold selectivity over human Na V 1.1, Na V 1.3, Na V 1.4, Na V 1.5, Na V 1.8, and Na V 1.9 channels. PTx2-3127 inhibits Na V 1.7 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 Na V 1.7 channels have transformative potential to define a new class of biologics to treat pain.