• Justin K Murray, Joseph Ligutti, Dong Liu, Anruo Zou, Leszek Poppe, Hongyan Li, Kristin L Andrews, Bryan D Moyer, Stefan I McDonough, Philippe Favreau, Reto Stöcklin, and Les P Miranda.
• Departments of Therapeutic Discovery, ‡Neuroscience, and §Pharmacokinetics & Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
• J. Med. Chem. 2015 Mar 12; 58 (5): 2299-314.

AbstractNaV1.7 is a voltage-gated sodium ion channel implicated by human genetic evidence as a therapeutic target for the treatment of pain. Screening fractionated venom from the tarantula Grammostola porteri led to the identification of a 34-residue peptide, termed GpTx-1, with potent activity on NaV1.7 (IC50 = 10 nM) and promising selectivity against key NaV subtypes (20× and 1000× over NaV1.4 and NaV1.5, respectively). NMR structural analysis of the chemically synthesized three disulfide peptide was consistent with an inhibitory cystine knot motif. Alanine scanning of GpTx-1 revealed that residues Trp(29), Lys(31), and Phe(34) near the C-terminus are critical for potent NaV1.7 antagonist activity. Substitution of Ala for Phe at position 5 conferred 300-fold selectivity against NaV1.4. A structure-guided campaign afforded additive improvements in potency and NaV subtype selectivity, culminating in the design of [Ala5,Phe6,Leu26,Arg28]GpTx-1 with a NaV1.7 IC50 value of 1.6 nM and >1000× selectivity against NaV1.4 and NaV1.5.

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