Title:Development of Allosteric Modulators of Voltage-Gated Na+ Channels: A Novel Approach for an Old Target
Volume: 21
Issue: 10
Author(s): Nolan M. Dvorak, Paul A. Wadsworth, Pingyuan Wang, Jia Zhou and Fernanda Laezza*
Affiliation:
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas, 77555,United States
Keywords:
Sodium channels, Selectivity, Protein:protein interaction, Allosteric modulators, Channelopathies, Drug discovery.
Abstract: Given their primacy in governing the action potential (AP) of excitable cells, voltage-gated
Na+ (Nav) channels are important pharmacological targets of therapeutics for a diverse array of
clinical indications. Despite historically being a traditional drug target, therapeutics targeting Nav
channels lack isoform selectivity, giving rise to off-target side effects. To develop isoform-selective
modulators of Nav channels with improved target-specificity, the identification and pharmacological
targeting of allosteric sites that display structural divergence among Nav channel isoforms
represents an attractive approach. Despite the high homology among Nav channel α subunit isoforms
(Nav1.1-Nav1.9), there is considerable amino acid sequence divergence among their constituent
C-terminal domains (CTD), which enables structurally and functionally specific protein:
protein interactions (PPI) with auxiliary proteins. Although pharmacological targeting of such PPI
interfaces between the CTDs of Nav channels and auxiliary proteins represents an innovate approach
for developing isoform-selective modulators of Nav channels, appreciable modulation of
PPIs using small molecules has conventionally been difficult to achieve. After briefly discussing
the challenges of modulating PPIs using small molecules, this current frontier review that follows
subsequently expounds on approaches for circumventing such difficulties in the context of developing
small molecule modulators of PPIs between transmembrane ion channels and their auxiliary
proteins. In addition to broadly discussing such approaches, the implementation of such approaches
is specifically discussed in the context of developing small molecule modulators between the CTD
of Nav channels and auxiliary proteins. Developing allosteric modulators of ion channels by targeting
their PPI interfaces with auxiliary proteins represents an innovative and promising strategy in
ion channel drug discovery that could expand the “druggable genome” and usher in first-in-class
PPI-targeting therapeutics for a multitude of channelopathies.
