痙攣和肌肉僵硬藥物開發前景
作者:
小柯機器人發布時間:2020/10/10 14:17:44
匈牙利MTA-ELTE馬達藥理學研究組András Málnási-Csizmadia和Máté Gyimesi研究組合作取得最新進展。他們揭示骨骼肌肌球蛋白的單一殘基變異使針對痙攣和肌肉僵硬的直接和選擇性藥物靶向成為可能。相關論文於2020年10月8日發表於國際頂尖學術期刊《細胞》。
他們確定了位於功能區通信中心的這些肌球蛋白同工型之間的關鍵殘基差異,這使他們可以設計選擇性抑制劑MPH-220。突變分析和MPH-220結合的骨骼肌肌球蛋白的原子結構證實了特異性的機制。通過MPH-220靶向骨骼肌肌球蛋白,可以在人和模型系統中實現肌肉鬆弛,而沒有心血管副作用,並且在疾病模型中腦損傷後改善痙攣性步態障礙。MPH-220提供了潛在的獨立於神經系統的選擇,以治療痙攣和肌肉僵硬。
研究人員表示,神經系統損傷和痛苦的下背部痙攣後的肌肉痙攣影響了全球超過10%的人口。當前的藥物功效有限,並會引起神經和心血管方面的副作用,因為它們靶向肌肉收縮的上遊調控子。直接抑制肌球蛋白可以提供最佳的肌肉鬆弛。然而,靶向骨骼肌肌球蛋白由於與心臟同工型相似而特別具有挑戰性。
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
Cell:《細胞》,創刊於1974年。隸屬於細胞出版社,最新IF:36.216