期刊
ACS CHEMICAL BIOLOGY
卷 16, 期 11, 页码 2164-2173出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.1c00067
关键词
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资金
- National Institute of Neurological Disorders and Stroke
- National Institute on Drug Abuse [NS096833]
Novel skeletostatins, derivatives of blebbistatin, show 40- to 170-fold selectivity for SkMII over other myosin II family members. They exhibit improved potency, solubility, and photostability, and have potential as useful probes for basic research and drug development.
Myosin IIs, actin-based motors that utilize the chemical energy of adenosine 5'-triphosphate (ATP) to generate force, have potential as therapeutic targets. Their heavy chains differentiate the family into muscle (skeletal [SkMII], cardiac, smooth) and nonmuscle myosin IIs. Despite the therapeutic potential for muscle disorders, SkMII-specific inhibitors have not been reported and characterized. Here, we present the discovery, synthesis, and characterization of skeletostatins, novel derivatives of the pan-myosin II inhibitor blebbistatin, with selectivity 40- to 170-fold for SkMII over all other myosin II family members. In addition, the skeletostatins bear improved potency, solubility, and photostability, without cytotoxicity. Based on its optimal in vitro profile, MT-134's in vivo tolerability, efficacy, and pharmacokinetics profile, tolerability, efficacy, pharmacokinetics were determined. MT-134 was well-tolerated in mice, impaired motor performance, and had excellent exposure in muscles. Skeletostatins are useful probes for basic research and a strong starting point for drug development.
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