PT  - JOURNAL ARTICLE
AU  - Laszlo Radnai
AU  - Matthew Surman
AU  - Madalyn Hafenbreidel
AU  - Erica J. Young
AU  - Rebecca F. Stremel
AU  - Li Lin
AU  - Paolo Pasetto
AU  - Xiaomin Jin
AU  - Mackenzie Geedy
AU  - Joni-Rae Partridge
AU  - Aagam Patel
AU  - Michael Conlon
AU  - James R. Sellers
AU  - Michael D. Cameron
AU  - Gavin Rumbaugh
AU  - Patrick R. Griffin
AU  - Theodore M. Kamenecka
AU  - Courtney A. Miller
TI  - Discovery of a Novel, Selective and Short-Acting Skeletal Myosin II Inhibitor
AID  - 10.1101/2020.07.28.225383
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.07.28.225383
4099  - http://biorxiv.org/content/early/2020/07/29/2020.07.28.225383.short
4100  - http://biorxiv.org/content/early/2020/07/29/2020.07.28.225383.full
AB  - Myosin IIs, actin-based motors that utilize the chemical energy of 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 therapeutic potential for muscle disorders, no SkMII-specific inhibitor has 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 within the myosin IIs for SkMII. In addition, the skeletostatins bear improved potency, solubility and photostability, without cytotoxicity. Based on its optimal in vitro profile, Skeletostatin 1’s in vivo tolerability, efficacy and pharmacokinetics were determined. Skeletostatin 1 was well-tolerated in mice, impaired motor performance, and had an excellent muscle to plasma ratio. Skeletostatins are useful probes for basic research and a strong starting point for drug development.Competing Interest StatementThe authors have declared no competing interest.