Development of ProTx-II Analogues as Highly Selective Peptide Blockers of Nav1.7 for the Treatment of Pain

Targeting ion channels involved in nociception is currently being investigated for the treatment of pain. Human genetic studies have demonstrated that patients with null mutations in the voltage-gated sodium channel Nav1.7 were resistant to pain suggesting that Nav1.7 could be a target for the development of novel analgesic. ProTx-II, a peptide toxin belonging to the inhibitory cystine knot (ICK) family, was shown to selectively block the Nav1.7 channel but lacked in vivo efficacy.

The IRBM Peptide Chemistry Group in collaboration with the team at Merck &Co., has recently published a manuscript on Journal of Medicinal Chemistry describing the design of analogs of ProTx-II-NH2 that block Nav 1.7 channel in vivo at tolerated doses and show efficacy in a thermal nociceptive animal model. The ProTx-II peptide scaffold was modified via amino acid substitutions to both improve selectivity in vitro and reduce the capability to trigger mast cell degranulation, a non IgE-mediated anaphylactoid reaction. Modified ProTx-II peptides were able to distribute to the target in nerves after subcutaneous dosing in rat, resulting in an observable increase in latency of response to thermal stimuli.