Treating Non-Dystrophic Myotonias: A Review Guiding the Design of Nav 1.4-Selective Sodium Channel Inhibitors
Open Access
Author:
Nerz, Kyle
Area of Honors:
Kinesiology
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
Tarkeshwar Singh, Thesis Supervisor Jonas Rubenson, Thesis Honors Advisor
Keywords:
Non-dystrophic myotonias Voltage-gated sodium ion channels Sodium channel blockers Movement disorders Drug design
Abstract:
Non-dystrophic myotonias are rare, skeletal muscle channelopathies that result in muscular stiffness and subsequently compromise motor control. These disorders arise from gain-of-function mutations in the voltage-gated sodium channel isoform, Nav 1.4. As such, current treatments for non-dystrophic myotonias include sodium channel blockers. Despite their efficacies, these drugs lack selectivity for Nav 1.4, thereby increasing patient risk for adverse, systemic side effects. By developing Nav 1.4-specific sodium channel inhibitors, however, the side effects associated with non-selective sodium channel blockers can be avoided. This, in turn, would offer patients with non-dystrophic myotonias a safe and efficacious treatment option. However, the development of isoform-specific sodium channel inhibitors has been a challenge. To guide the design of Nav 1.4-selective inhibitors that can be used to treat non-dystrophic myotonias, this review explored the literature surrounding voltage-gated sodium channels, recent discoveries of Nav 1.7-selective inhibitors, along with Nav 1.4’s role in skeletal muscle. Through this examination, it was proposed that prospective Nav 1.4-selective inhibitors must (1) contain a negatively charged structural moiety and (2) compliment isoform-specific amino acid residues in the channel’s voltage-sensing domain.
