A painful tale about synthetic scorpion toxins

Within the voltage-gated NaC (Nav) channel gene family, the Nav1.7 isoform (SCN9A) has been receiving a great deal of scientific and clinical attention after investigators uncovered its strategic role in various pain syndromes. As a result, Nav1.7 became somewhat of a Holy Grail for researchers in academia as well as the pharmaceutical industry who are interested in discovering novel, target-specific non-narcotic pain therapeutics. However, clinically-used Nav channel drugs are prone to dose-limiting side effects because they typically target the conserved pore region and therefore do not discriminate between isoforms. In contrast, Nav channel voltage-sensing domains (VSDs) differ substantially between isoforms and regulate pore opening and closing (i.e. gating). As such, it should be possible to design effective drugs that target the gating process of a particular Nav channel isoform without physically blocking the pore, a fascinating concept that has recently led to the discovery of Nav1.7-specific small-molecule compounds. 4,5