Development of the specific inhibitor for skeletal musle myosin light chain kinase

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K15366
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Osaka University
• Principal Investigator: Oya Ryohei 大阪大学, 医学部附属病院, 医員 (50728053)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 骨格筋型ミオシン軽鎖キナーゼ / 化合物スクリーニング / 酵素活性測定 / 筋萎縮性側索硬化症 / 神経筋疾患

Outline of Final Research Achievements

The muscle disease is hard to treat and the development of a new medicine is necessary to improve muscle function. The phosphorylation of myosin regulatory light chain by skeletal muscle myosin light chain kinase (skMLCK) is important for muscle contraction. To activate or inhibit skMLCK may induce to increase or reduce the force produced by skeletal muscle, respectively.
In our present study, we performed the high throughput screening for skMLCK activator or inhibitor using Tokyo university low molecular weight compounds full library. And we finally found the 106 candidates of activator and 12 candidates of inhibitor. Furthermore, we constructed the measurement system of muscle force, and successfully showed that the skMLCK gene transfer using adeno associated vector induced the increment of muscle force in SOD mouse (which is the model mouse of amyotrophic lateral sclerosis).

Free Research Field

耳鼻咽喉科頭頸部外科学

Academic Significance and Societal Importance of the Research Achievements

筋収縮力に異常をきたす疾患は多く存在する。脳梗塞後の痙縮では筋収縮の亢進が、神経筋疾患では低下がみられるが、それらには有効な治療薬が存在しない。本研究では、skMLCKの作用を活性化、もしくは阻害することでこれらの疾患の治療につながる可能性が示唆された。また治療薬を開発するうえで活性化剤、阻害剤の候補となる低分子化合物の同定に成功した。これらの化合物の解析を進めることで新規治療薬の開発へとつながると考えられる。