Drug Discovery for Skeletal Muscle Channelopathies

Creative Bioarray is dedicated to helping clients develop drugs for skeletal muscle channelopathies (SMC), including non-dystrophic myotonias (NDM), periodic paralysis (PP), myasthenic syndromes, and congenital myopathies. We aim to reduce muscle excitability in NDM or alter triggers of attacks in PP to help clients develop highly effective drugs.

Introduction

Ion channels play important roles in skeletal muscle fibers, including regulating muscle excitability, excitation-contraction coupling, and contraction. Mutations in genes encoding voltage-gated chloride, calcium, sodium, and potassium channels in skeletal muscle cell membranes often lead to a group of SMC with phenotypic and genetic heterogeneity. Genetic mutations in these channels may have a variety of effects on muscle function, ranging from sarcolemma inexcitability (flaccid paralysis, muscle weakness, fatigue) to hyperexcitability (myotonia, muscle stiffness, spasticity), and on muscle integrity with diverse myopathic traits.

SMC is divided into NDM and PP according to the level of sarcolemmal excitability. Hereditary factor is one of the important causes of SMC. Molecular genetic studies have found a number of related pathogenic genes, including SCN4A (Na_v1.4), CACNA1S (Ca_v1.1), KCNJ2 (Kir2.1), KCNJ6 (Kir2.6), and CLCN1 (ClC-1). Mastering important information on the molecular mechanisms by which mutations alter ion channel function could help accelerate the entry into a new era of precision medicine for SMC.

Fig. 1 The skeletal muscle channelopathies—causative genes, dysfunctional ion channel, and resultant clinical symptom. (Matthews, 2021)

Drug Development for NDM

NDM includes myotonia congenita (MC), paramyotonia congenita (PMC), and sodium channel myotonia (SCM). Symptomatic (MC) and targeted (PMC and SCM) treatments are designed to reduce skeletal muscle hyperexcitability. Our drug development services include, but are not limited to:

Repurposing of marketed Na_v blockers.
Development of drugs that enhance slow inactivation of Nav channels.
Development of ClC-1 channel activators and pharmacological chaperones.
Develop Na_v blockers with advantages of selectivity and use-dependency.
Development of pharmacogenetics strategies.

Drug Development for PP

PP includes hyperkalemic periodic paralysis (HyperPP), hypokalemic periodic paralysis types 1 and 2 (HypoPP1 and 2), tyreotoxic periodic paralysis, and Andersen-Tawil syndrome. Symptomatic treatment aims at reducing the frequency and severity of paralytic attacks and restoring serum K⁺ levels. Our drug development services include, but are not limited to:

Development of guanidinium derivatives and other Igp blockers for HypoPP1 and 2.
Development of drugs that may increase BK channel activity and ClC-1 channel opening.
Development of selective KATP openers for skeletal muscle channels.
Development of drugs that activate Na⁺/K⁺-ATPase and restore serum K⁺ levels in HyperPP.

Creative Bioarray focuses on the regulation of ion channels to help clients develop drugs to treat skeletal muscle diseases caused by channel dysfunction. Our state-of-the-art platforms, seasoned scientists, and global facilities can support your drug discovery programs. If you are interested in our services, please contact us for more details.

Reference

Matthews, E.; et al. Skeletal muscle channelopathies: a guide to diagnosis and management. Practical Neurology, 2021, 21(3): 196-204.

For Research Use Only.