Total Synthesis of Photoswitchable Latrunculin B Enables Reversible Inhibition of Actin Polymerization and Cell Migration

The actin cytoskeleton is involved in numerous cell properties like cell shape, contraction, division, or migration. All are controlled by subtle regulation mechanisms involving actin-binding proteins, and affecting the growth of filaments through the polymerization of free actin monomers. The filament growth can also be inhibited by small molecules like latrunculin B, a natural product that sequesters monomeric actin, thus preventing its polymerization. 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 envisioned the development of photoswitchable latrunculin B, prepared by a total synthesis approach allowing the introduction of a light-responsive azobenzene moiety. One of these modified latrunculins proved to have excellent photophysical properties, with good photostationary states (ca. 90/10 in the two reversible states), long half-lives and no observable fatigue resistance during reversible photoswitching performed at 370 nm and 440 nm. We demonstrate that the Z-photoisomer induces a pronounced inhibition of the growth of single actin filaments in vitro, comparatively to the E-isomer, and this behavior was rationalized by docking studies. Most importantly, this inhibition was photoinduced in migrating cells, stopping actin-based membrane dynamics. This inhibition was reversible upon irradiation at 440 nm. Furthermore, it could be induced locally in a single cell.