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Computational design of peptides to target Na1.7 channel with high potency and selectivity for the treatment of pain. | LitMetric
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 1000-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.
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