Modulating Protein-Protein Interactions with Visible-Light-Responsive Peptide Backbone Photoswitches
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Life relies on a myriad of carefully orchestrated processes, in which proteins and their direct interplay ultimately determine cellular function and disease. Modulation of this complex crosstalk has recently attracted attention, even as a novel therapeutic strategy. Herein, we describe the synthesis and characterization of two visible-light-responsive peptide backbone photoswitches based on azobenzene derivatives, to exert optical control over protein-protein interactions (PPI). The novel peptidomimetics undergo fast and reversible isomerization with low photochemical fatigue under alternatively blue-/green-light irradiation cycles. Both bind in the nanomolar range to the protein of interest. Importantly, the best peptidomimetic displays a clear difference between isomers in its protein-binding capacity and, in turn, in its potential to inhibit enzymatic activity through PPI disruption. In addition, crystal structure determination, docking and molecular dynamics calculations allow a mo...lecular interpretation and open up new avenues in the design and synthesis of future photoswitchable PPI modulators.
Keywords:azobenzenes / isomerization / peptidomimetics / photochemistry / protein-protein interactions
Source:Chembiochem, 2019, 20, 11, 1417-1429
- Wiley-VCH Verlag GMBH, Weinheim