NaV1.7 is a voltage-gated sodium ion channel implicated by human genetic evidence as a therapeutic target for pain. This talk details our efforts in identifying NaV1.7 inhibitors using peptide hits from venom screens. We discovered novel disulfide-rich toxin peptides from tarantula venom containing an inhibitory cystine knot folded motif. Attribute-based positional scans of native residues followed by putative binding face SAR aided by rational molecular docking further improved the potency and selectivity of the native scaffold. Electrophysiology characterization and X-ray crystallography of the lead peptide and its activity in a NaV1.7-dependent in vivo behavior model will be described.

Discovery of tarantula venom-derived NaV1.7-inhibitory peptide with systemic block of histamine-induced pruritis

256th National Meeting (2018)

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