Single Residue Variation in Skeletal Muscle Myosin Enables Direct and Selective Drug Targeting for Spasticity and Muscle Stiffness.
Single Residue Variation in Skeletal Muscle Myosin Enables Direct and Selective Drug Targeting for Spasticity and Muscle Stiffness.
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DOI：
10.1016/j.cell.2020.08.050
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发表时间：
2020-10-15
期刊：
影响因子：
64.5
通讯作者：
Málnási-Csizmadia A
中科院分区：
文献类型：
--
作者：
Gyimesi M;Horváth ÁI;Túrós D;Suthar SK;Pénzes M;Kurdi C;Canon L;Kikuti C;Ruppel KM;Trivedi DV;Spudich JA;Lőrincz I;Rauscher AÁ;Kovács M;Pál E;Komoly S;Houdusse A;Málnási-Csizmadia A
神经系统损伤后的肌肉痉挛和疼痛性腰部痉挛影响着全球 10% 以上的人口。目前的药物疗效有限，并且会引起神经和心血管副作用，因为它们针对的是肌肉收缩的上游调节因子。直接肌球蛋白抑制可以提供最佳的肌肉松弛效果，然而，针对骨骼肌球蛋白特别具有挑战性，因为它与心脏亚型相似。我们确定了这些肌球蛋白异构体之间的一个关键残基差异，位于功能区的通讯中心，这使我们能够设计一种选择性抑制剂 MPH-220。诱变分析和 MPH-220 结合骨骼肌肌球蛋白的原子结构证实了特异性机制。 MPH-220 靶向骨骼肌肌球蛋白，可在人类和模型系统中实现肌肉松弛，且不会产生心血管副作用，并改善疾病模型中脑损伤后的痉挛步态障碍。 MPH-220 提供了一种潜在的独立于神经系统的选择来治疗痉挛和肌肉僵硬。目前，治疗性肌肉松弛是通过间接机制、通过调节神经系统在药理学上实现的。选择性靶向骨骼肌还不可能，因为骨骼肌和心脏中的肌球蛋白同种型在结构上非常相似。 Gyimesi 等人使用理性的、基于结构的方法。设计一种小分子肌肉松弛剂，专门抑制骨骼肌球蛋白 2 亚型，但不抑制心脏肌球蛋白 2 亚型。通过他们的新候选药物，他们展示了如何通过药物缓解痉挛和肌肉僵硬，而不会对心脏或神经系统产生副作用。
Muscle spasticity after nervous system injuries and painful low back spasm affect more than 10% of global population. Current medications are of limited efficacy and cause neurological and cardiovascular side effects because they target upstream regulators of muscle contraction. Direct myosin inhibition could provide optimal muscle relaxation, however, targeting skeletal myosin is particularly challenging because of its similarity to the cardiac isoform. We identified a key residue difference between these myosin isoforms, located in the communication center of the functional regions, which allowed us to design a selective inhibitor, MPH-220. Mutagenic analysis and the atomic structure of MPH-220-bound skeletal muscle myosin confirmed the mechanism of specificity. Targeting skeletal muscle myosin by MPH-220 enabled muscle relaxation, in human and model systems, without cardiovascular side effects and improved spastic gait disorders after brain injury in a disease model. MPH-220 provides a potential nervous system-independent option to treat spasticity and muscle stiffness. Therapeutic muscle relaxation is currently achieved pharmacologically via indirect mechanisms, by modulation of the nervous system. Selective targeting of skeletal muscle has not been possible because myosin isoforms in skeletal muscle and the heart are structurally very similar. Using a rational, structure-based approach, Gyimesi et al. design a small molecule muscle relaxant that specifically inhibits the skeletal, but not the cardiac, myosin 2 isoform. With their new drug candidate, they show how spasticity and muscle stiffness might be relieved pharmacologically without cardiac or nervous system side effects.
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影响因子：
13.6
作者：
Kawana M;Sarkar SS;Sutton S;Ruppel KM;Spudich JA
通讯作者：
Spudich JA
DOI：
10.1074/jbc.m110.212290
发表时间：
2011-06-17
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
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通讯作者：
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影响因子：
2.6
作者：
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通讯作者：
Watson, Linda
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
4.8
作者：
Gyimesi, Mate;Kintses, Balint;Malnasi-Csizmadia, Andras
通讯作者：
Malnasi-Csizmadia, Andras