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

• DOI: 10.7554/elife.81727
• Publication Date: 2022-12-28T13:02:46Z
• Authors: Phuong T Nguyen; Hai M Nguyen; Karen M Wagner; Robert G 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-Ya...
• Keywords: NAV1; Nociceptor; Nav1.5; Mediator

The voltage-gated sodium NaV1.7 channel plays a key role as mediator of action potential propagation in C-fiber nociceptors and is an established molecular target for pain therapy. ProTx-II potent moderately selective peptide toxin from tarantula venom that inhibits human activation. Here we used available structural experimental data to guide Rosetta design ProTx-II-based inhibitors channels. Functional testing designed peptides using electrophysiology identified the PTx2-3127 PTx2-3258 with IC50s 7 nM 4 hNaV1.7 more than 1000-fold selectivity over NaV1.1, NaV1.3, NaV1.4, NaV1.5, NaV1.8, NaV1.9 currents mouse sensory neurons shows efficacy rat models chronic thermal when administered intrathecally. Rationally channels have transformative define new class biologics treat pain.