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.

神经系统损伤后的肌肉痉挛和疼痛的下背部痉挛影响了全球 10% 以上的人口。目前的药物疗效有限，并会导致神经和心血管副作用，因为它们针对肌肉收缩的上游调节器。直接肌球蛋白抑制可以提供最佳的肌肉放松；然而，靶向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同工型之间的关键残基差异，位于功能区域的通讯中心，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。通过 MPH-220 靶向骨骼肌肌球蛋白，使肌肉放松，在人类和模型系统中，在疾病模型中没有心血管副作用和改善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。