Discovery of a Small Molecule-Dependent Photolytic Peptide.

We accidentally found that YM-53601, a known small-molecule inhibitor of squalene synthase (SQS), selectively depletes SQS from mammalian cells upon ultraviolet (UV) irradiation. Further analyses indicate that the photo-depletion of SQS requires its short peptide segment located at the COOH terminus. Remarkably, when the 27-amino acid peptide was fused to GFP or unrelated proteins at either NH2 or COOH termini, such fusion proteins were selectively depleted when the cells are treated both with YM-53601 and UV exposure. Product analysis and ESR experiments suggest that the UV irradiation promotes a homolytic C-O bond cleavage of the aryl ether group in YM-53601. It is likely that the radical species generated from UV-activated YM-53601 abstract hydro-gen atoms from the SQS peptide, leading to the photolysis of the entire protein. The pair of the SQS peptide and YM-53601 discovered in the present study paves the way for designing a new small-molecule-controlled optogenetic tool.