Nav1.7 Inhibitor

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The Technology Researchers at the Institute for Molecular Bioscience (IMB) at The University of Queensland (UQ) have developed a novel peptide-based inhibitor of the voltage-gated sodium channel 1.7 (Nav1.7). Navs are integral membrane proteins that allow influx of sodium ions, which is essential for action potential generation and propagation in electrically excitable cells. Mammalian Nav channels consist of nine subtypes (Nav1.1-1.9) that have distinct expression profiles and subsequent functional roles, with compelling genetic evidence linking Nav1.7 to pain. Loss-of-function mutations of SCN9A, the gene encoding Nav1.7, have been identified as the cause of congenital insensitivity to pain, a rare condition characterized by the inability to sense pain in otherwise normal individuals, although anosmia (absence of sense of smell) is reported. Gain-of-function mutations of SCN9A are the cause of two hereditary pain disorders, inherited erythromelalgia and paroxysmal extreme pain disorder. Both disorders are associated with redness, swelling and burning pain. Thus, pharmacological inhibition of Nav1.7 is a promising therapeutic strategy for the treatment pain. Developing analgesics with Nav1.7 selectivity is essential, as activity at major off-targets, including the skeletal muscle isoform Nav1.4, the cardiac isoform Nav1.5, and the neuronal isoforms Nav1.1, Nav1.2 and Nav1.6, is likely to cause dose-limiting adverse effects. However, it is difficult to selectively target one Nav subtype over the others due to high sequence identity (>50%), particularly in the pore forming segments, where most small molecules, such as local anaesthetics bind. Venom-derived peptides usually bind to the less conserved gate forming segments or voltage sensor domains, and therefore often achieve unparalleled selectivity compared to small molecules. The UQ peptide termed Pn3a is a potent inhibitor of Nav1.7 with an IC50 of 0.9nM. It is 35 residues in size, and has been extensively characterised in in vitro and in vivo assays. In whole-cell patch-clamp experiments, Pn3a demonstrates 40-fold selectivity over Nav1.1, 100-fold selectivity over Nav1.2, 1.3, 1.4 and 1.6, and 900-fold selectivity over Nav1.5, 1.8, and 1.9.   Proof of concept The Pn3a peptide has been evaluated in several rodent pain models, including a post-surgical pain model. When administered systemically by intraperitoneal injection (i.p.) as a single dose, the peptide demonstrated: • Induction of full analgesia with significantly increased withdrawal thresholds that were not statistically different from naïve animals before surgery; • Comparable efficacy to the same dose of oxycodone and significantly improved efficacy over Pfizer’s small molecule inhibitor of Nav1.7 PF04856264 that previously entered clinical development; and • No effect on motor coordination.