Visible-Light-Switchable Molecular Glues for Reversible Control of Protein Function

Chemically induced dimerization/proximity (CID/CIP) systems controlled by chemical dimerizers (also known as molecular glues) provide valuable means for understanding and manipulating complex, dynamic biological systems. In this study, we present the development of versatile chemo-optogenetic systems utilizing azobenzene-based photoswitchable molecular glues (sMGs) for reversible protein dimerization controlled by visible light. These systems allow multiple cycles of light-induced dimerization, overcoming the limitations of irreversible photolysis in previous systems. Through optimizing photoswitch properties and linker strategies, we achieved efficient and reversible control using blue, green, and red light. We demonstrate that these systems enable rapid and reversible control of protein function in vitro and in cells. The findings represent a significant advancement in chemo-optogenetics, offering opportunities to expand applications requiring precise spatiotemporal regulation of dynamic biological processes.