A Multifunctional and Secure Photoresponsive Proteasome Inhibitor to Control Cell Fate

Abstract

Precise external control of biological processes represents a central interest in the life sciences. Specifically designed molecular tools are ideally suited for this purpose and consequently have found widespread applications including fundamental studies in biology or pharmaceutical drug development. Introducing photoresponsiveness to modulate the biological activity of a molecule offers heightened levels of control by adding adjustable spatial and temporal resolution. Here we present the next leap in capabilities in which the photoresponsiveness of a small molecule inhibitor is coupled to a customizable secondary function. This multifunctional photopharmacological tool is based on MG132─a potent proteasome inhibitor─whose activity is securely photocaged and thus rendered fully light-responsive. At the same time, an alkyne group is introduced into the structure allowing for facile late-stage attachment of a second functionality via simple click chemistry. The heightened utility is showcased by stably linking a fluorophore, allowing to monitor the spatial distribution of the photoactivatable inhibitor within living cells. This multilevel photoresponsive molecular tool opens up a vast space of opportunities for programmable and customizable biological activity control.