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 molecular interpretation and open up new avenues in the design and synthesis of future photoswitchable PPI modulators.

The front cover picture confronts the two different states of a visible‐light photoswitchable peptide in complex with the WDR5 protein. The green background represents the 520 nm irradiation, which leads the cis isomer, whereas the blue one illustrates the 405 nm irradiation for the trans isomer. In our paper, we describe two novel peptide backbone photoswitches capable of disrupting epigenetic protein–protein interactions differently upon visible‐light illumination. We believe that these building blocks will find applications beyond protein control. More information can be found in the full paper by O. Vázquez et al. on page 1417 in Issue 11, 2019 (DOI: 10.1002/cbic.201800737).