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Modulating Protein-Protein Interactions with Visible-Light Responsive Peptide Backbone Photoswitches
摘要： Life relies on a myriad of carefully orchestrated processes, in which proteins and their direct interplay ultimately determine cellular function and disease. Modulation of these complex cross-talks has recently attracted attention, even as a novel therapeutic strategy. Here, 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). Our novel peptidomimetics undergo fast isomerization and reversibility with low photochemical fatigue under alternatively blue/green-light irradiation cycles. Both bind in the nanomolar rage to the protein of interest. Importantly, our best peptidomimetic displays a clear difference between isomers in its protein-binding capacity and, in turn, in its potential to inhibit enzymatic activity via PPI disruption. In addition, crystal structure determination, docking and MD calculations give a molecular interpretation and open new avenues in the design and synthesis of future photoswitchable PPI modulators.
关键词： protein-protein interactions,photopharmacology,visible-light irradiation,azobenzene,photoswitches
更新于2025-11-21 11:20:42
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Hemithioindigos for cellular photopharmacology: desymmetrised molecular switch scaffolds enabling design control over the isomer-dependency of potent antimitotic bioactivity
摘要： Druglike small molecules with photoswitchable bioactivity – photopharmaceuticals – allow biologists to perform studies with exquisitely precise and reversible, spatial and temporal control over critical biological systems inaccessible to genetic manipulation. The photoresponsive pharmacophores disclosed have been almost exclusively azobenzenes, which has limited the structural and substituent scope of photopharmacology. More detrimentally, for azobenzene reagents, it is not researchers’ needs for adapted experimental tools, but rather protein binding site sterics, that typically force whether the trans (dark) or cis (lit) isomer is the more bioactive. We now present first hemithioindigo-based pharmacophores enabling photoswitchable control over endogenous biological activity in cellulo. HOTubs optically control microtubule depolymerisation and cell death in unmodified mammalian cells. Notably, we show how the asymmetry of hemithioindigos allows a priori design of either Z- or E- (dark- or lit)-toxic antimitotics, whereas the corresponding azobenzenes are exclusively lit-toxic. We thus demonstrate that hemithioindigos enable an important expansion of the substituent and design scope of photopharmacological interventions for biological systems.
关键词： Photopharmacology,Drug design,Photochromism,Cytoskeleton,Antiproliferation
更新于2025-09-23 15:23:52
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Light-wavelength-based Quantitative Control of Dihydrofolate Reductase Activity Using Photochromic Isostere of Inhibitor
摘要： Photopharmacology has attracted research attention as a new tool to achieve the optical control of biomolecules following the methods of caged compounds and optogenetics. We have developed an efficient photopharmacological inhibitor, azoMTX, for Escherichia coli dihydrofolate reductase (eDHFR) by replacing some atoms of the original ligand, methotrexate, to obtain the photoisomerization property. This fine molecular design enabled the quick structural conversion between the active 'bent' Z-isomer and the inactive 'extended' E-isomer of azoMTX, and this property afforded quantitative control of the enzyme activity, depending on the wavelength of irradiated light. The real-time photoreversible control of enzyme activity was also achieved.
关键词： methotrexate,photochromism,enzymes,azobenzene,photopharmacology
更新于2025-09-19 17:15:36