Light-controlled micron-scale molecular motion.

The micron-scale movement of biomolecules along supramolecular pathways, mastered by nature, is a remarkable system requiring strong yet reversible interactions between components under the action of a suitable stimulus. Responsive microscopic systems using a variety of stimuli have demonstrated impressive relative molecular motion. However, locating the position of a movable object that travels along self-assembled fibres under an irresistible force has yet to be achieved. Here, we describe a purely supramolecular system where a molecular 'traveller' moves along a 'path' over several microns when irradiated with visible light. Real-time imaging of the motion in the solvated state using total internal reflection fluorescence microscopy shows that anionic porphyrin molecules move along the fibres of a bis-imidazolium gel upon irradiation. Slight solvent changes mean movement and restructuring of the fibres giving microtoroids, indicating control of motion by fibre mechanics with solvent composition. The insight provided here may lead to the development of artificial travellers that can perform catalytic and other functions.

Discovery of Selective Inhibitors for In Vitro and In Vivo Interrogation of Skeletal Myosin II.

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 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.