当前位置:科学网首页 > 小柯机器人 >详情
痉挛和肌肉僵硬药物开发前景
作者:小柯机器人 发布时间:2020/10/10 14:17:44

匈牙利MTA-ELTE马达药理学研究组András Málnási-Csizmadia和Máté Gyimesi研究组合作取得最新进展。他们揭示骨骼肌肌球蛋白的单一残基变异使针对痉挛和肌肉僵硬的直接和选择性药物靶向成为可能。相关论文于2020年10月8日发表于国际顶尖学术期刊《细胞》。

他们确定了位于功能区通信中心的这些肌球蛋白同工型之间的关键残基差异,这使他们可以设计选择性抑制剂MPH-220。突变分析和MPH-220结合的骨骼肌肌球蛋白的原子结构证实了特异性的机制。通过MPH-220靶向骨骼肌肌球蛋白,可以在人和模型系统中实现肌肉松弛,而没有心血管副作用,并且在疾病模型中脑损伤后改善痉挛性步态障碍。MPH-220提供了潜在的独立于神经系统的选择,以治疗痉挛和肌肉僵硬。

研究人员表示,神经系统损伤和痛苦的下背部痉挛后的肌肉痉挛影响了全球超过10%的人口。当前的药物功效有限,并会引起神经和心血管方面的副作用,因为它们靶向肌肉收缩的上游调控子。直接抑制肌球蛋白可以提供最佳的肌肉松弛。然而,靶向骨骼肌肌球蛋白由于与心脏同工型相似而特别具有挑战性。

附:英文原文

Title: Single Residue Variation in Skeletal Muscle Myosin Enables Direct and Selective Drug Targeting for Spasticity and Muscle Stiffness

Author: Máté Gyimesi, ádám I. Horváth, Demeter Túrós, Sharad Kumar Suthar, Máté Pénzes, Csilla Kurdi, Louise Canon, Carlos Kikuti, Kathleen M. Ruppel, Darshan V. Trivedi, James A. Spudich, István Lrincz, Anna á. Rauscher, Mihály Kovács, Endre Pál, Sámuel Komoly, Anne Houdusse, András Málnási-Csizmadia

Issue&Volume: 2020-10-08

Abstract: Muscle spasticity after nervous system injuries and painful low back spasm affectmore than 10% of global population. Current medications are of limited efficacy andcause neurological and cardiovascular side effects because they target upstream regulatorsof muscle contraction. Direct myosin inhibition could provide optimal muscle relaxation;however, targeting skeletal myosin is particularly challenging because of its similarityto the cardiac isoform. We identified a key residue difference between these myosinisoforms, located in the communication center of the functional regions, which allowedus to design a selective inhibitor, MPH-220. Mutagenic analysis and the atomic structureof MPH-220-bound skeletal muscle myosin confirmed the mechanism of specificity. Targetingskeletal muscle myosin by MPH-220 enabled muscle relaxation, in human and model systems,without cardiovascular side effects and improved spastic gait disorders after braininjury in a disease model. MPH-220 provides a potential nervous-system-independentoption to treat spasticity and muscle stiffness.

DOI: 10.1016/j.cell.2020.08.050

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)31138-7

期刊信息
Cell:《细胞》,创刊于1974年。隶属于细胞出版社,最新IF:36.216
官方网址:https://www.cell.com/