Drug development for the treatment of RyR1-related skeletal muscle diseases

Abstract

Type 1 ryanodine receptor (RyR1) is an intracellular Ca²⁺ release channel on the sarcoplasmic reticulum of skeletal muscle, and it plays a central role in excitation-contraction (E-C) coupling. Mutations in RyR1 are implicated in various muscle diseases including malignant hyperthermia, central core disease, and myopathies. Currently, no specific treatment exists for most of these diseases. Recently, high-throughput screening (HTS) assays have been developed for identifying potential candidates for treating RyR-related muscle diseases. Currently, two different methods, namely a FRET-based assay and an endoplasmic reticulum Ca²⁺-based assay, are available. These assays identified several compounds as novel RyR1 inhibitors. In addition, the development of a reconstituted platform permitted HTS assays for E-C coupling modulators. In this review, we will focus on recent progress in HTS assays and discuss future perspectives of these promising approaches.