Total synthesis of photoswitchable latrunculin B enables reversible control of actin polymerization and cell migration
Résumé
The actin cytoskeleton plays a central role in regulating essential cellular properties such as cell shape, contraction, division, or migration. The filament growth, controlled by subtle regulation mechanisms, can also be inhibited by small molecules preventing actin polymerization, like latrunculin B. This compound has been widely used in cell biology to inhibit cytokinesis or cell migration. To further these applications and provide a mean for the spatiotemporal control of cell migration, we pre-pared photoswitchable latrunculin B through total synthesis, allowing the incorporation of a light-responsive azobenzene moiety. One of these modified latrunculins displayed excellent photophysical properties, with good photostationary states (ca. 90/10 in the two reversible states), long half-lives and excellent fatigue resistance during photoswitching, performed at 370 nm and 440 nm. The Z-photoisomer induced a significant inhibition of the growth of single actin filaments in vitro, com-paratively to the E-isomer—a reversible behavior that was rationalized through molecular docking. Most importantly, this inhibition was photoinduced in migrating cells, stopping actin-dependent membrane dynamics in a reversible manner, and was induced locally in a single cell.
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