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

IF 4 3区医学 Q1 PHARMACOLOGY & PHARMACY

Current Opinion in Pharmacology Pub Date : 2023-04-01 DOI:10.1016/j.coph.2023.102356

Takashi Murayama , Nagomi Kurebayashi , Ryosuke Ishida , Hiroyuki Kagechika

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引用次数: 2

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.

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治疗RyR1相关骨骼肌疾病的药物开发

1型赖氨酸受体（RyR1）是骨骼肌肌浆网上的细胞内Ca2+释放通道，在兴奋-收缩（E-C）偶联中发挥核心作用。RyR1的突变与各种肌肉疾病有关，包括恶性热疗、中枢核心疾病和肌病。目前，这些疾病大多没有特效治疗方法。最近，已经开发了高通量筛选（HTS）测定法来鉴定治疗RyR相关肌肉疾病的潜在候选者。目前，有两种不同的方法，即基于FRET的测定和基于内质网Ca2+的测定。这些测定确定了几种化合物为新型RyR1抑制剂。此外，重组平台的开发允许对E-C偶联调节剂进行HTS测定。在这篇综述中，我们将重点关注HTS分析的最新进展，并讨论这些有前景的方法的未来前景。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Current Opinion in Pharmacology 医学-药学

CiteScore

8.80

自引率

2.50%

发文量

131

审稿时长

4-8 weeks

期刊介绍： Current Opinion in Pharmacology (COPHAR) publishes authoritative, comprehensive, and systematic reviews. COPHAR helps specialists keep up to date with a clear and readable synthesis on current advances in pharmacology and drug discovery. Expert authors annotate the most interesting papers from the expanding volume of information published today, saving valuable time and giving the reader insight on areas of importance.