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.

Optical control has enabled functional modulation in cell culture with unparalleled spatiotemporal resolution. However, current tools for in vivo manipulation are scarce. Here, we design and implement a genuine on–off optochemical probe capable of achieving hematopoietic control in zebrafish. Our photopharmacological approach first developed c onformationally s trained vi sible light p hotoswitches (CS-VIPs) as inhibitors of the histone methyltransferase MLL1 (KMT2A). In blood homeostasis MLL1 plays a crucial yet controversial role. CS-VIP 8 optimally fulfils the requirements of a true bistable functional system in vivo under visible-light irradiation, and with unprecedented stability. These properties are exemplified via hematopoiesis photoinhibition with a single isomer in zebrafish. The present interdisciplinary study uncovers the mechanism of action of CS-VIPs. Upon WDR5 binding, CS-VIP 8 causes MLL1 release with concomitant allosteric rearrangements in the WDR5/RbBP5 interface. Since our tool provides on-demand reversible control without genetic intervention or continuous irradiation, it will foster hematopathology and epigenetic investigations. Furthermore, our workflow will enable exquisite photocontrol over other targets inhibited by macrocycles.

Cyclic 3′,5′-AMP (cAMP) and cyclic 3′,5′-GMP (cGMP) are both long known as important nucleotide secondary messengers in eukaryotes. This is also the case for cAMP in prokaryotes, whereas a signaling role for cGMP in this domain of life has been recognized only recently.

Cyclic AMP (cAMP) is a ubiquitous second messenger synthesized by most living organisms. In bacteria, it plays highly diverse roles in metabolism, host colonization, motility, and many other processes important for optimal fitness. The main route of cAMP perception is through transcription factors from the diverse and versatile CRP-FNR protein superfamily. Since the discovery of the very first CRP protein CAP in Escherichia coli more than four decades ago, its homologs have been characterized in both closely related and distant bacterial species. The cAMP-mediated gene activation for carbon catabolism by a CRP protein in the absence of glucose seems to be restricted to E. coli and its close relatives. In other phyla, the regulatory targets are more diverse. In addition to cAMP, cGMP has recently been identified as a ligand of certain CRP proteins. In a CRP dimer, each of the two cyclic nucleotide molecules makes contacts with both protein subunits and effectuates a conformational change that favors DNA binding. Here, we summarize the current knowledge on structural and physiological aspects of E. coli CAP compared with other cAMP- and cGMP-activated transcription factors, and point to emerging trends in metabolic regulation related to lysine modification and membrane association of CRP proteins.

α‐Bromosulfones have been synthesized diastereoselectively by reaction of β‐hydroxy gem‐dibromides with aromatic sulfinates. More steric demanding groups in the β‐position led to increased stereoselectivity in these SN2 reactions. Lithiated α‐bromosulfones react diastereoselectively with alkylating agents, aldehydes, and ketones. No configurational stability of the lithiated α‐bromosulfones was observed except fast equilibration towards a chelate‐stabilized intermediate. Treatment of the α‐bromosulfone with methylcuprate resulted in substitution of the bromine by a methyl group.

Reaction of β‐hydroxy gem‐dibromides with aromatic sulfinates leads to α‐bromosulfones in a diastereoselective manner.

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).

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