The use of fluorescent techniques in biological research is widespread. Many of the techniques rely on the use of fluorescent genetically-encoded tags (namely GFP and its different variants), but small molecules and nanoparticle-based approaches are being increasingly used. Peptides, owing to their modular nature, synthetic accessibility and biomolecular recognition potential, offer unique possibilities for the development of efficient and selective fluorescent sensors. In this tutorial review we present several of the strategies that have been used to develop fluorescent-based peptide sensors and discuss selected applications to biological problems.
Bioactive photoswitchable peptides as excellent optochemical tools for cellular processes.
We report the use of bioorthogonal reactions as an original strategy in photodynamic therapyt oa chieve conditional phototoxicity and specific subcellular localization simultaneously.O ur novel halogenated BODIPY-tetrazine probes only become efficient photosensitizers (F D % 0.50) through an intracellular inverse-electron-demand Diels-Alder reaction with as uitable dienophile.A binitio computations reveal an activation-dependent change in decaychannels that controls 1 O 2 generation. Our bioorthogonal approach also enables spatial control. As aproof-of-concept, we demonstrate the feasibility of the selective activation of our dormant photosensitizer in cellular nuclei, causing cancer cell death upon irradiation. Thus,o ur dual biorthogonal, activatable photosensitizers open new venues to combat current limitations of photodynamic therapy.Photodynamic therapy (PDT) is aw ell-established medical treatment for several maladies [1] that is based on the direct or indirect generation of cytotoxic reactive oxygen species (ROS) under exposure of ap hotosensitizer (PS) to light. [2] Light-controlled treatments,s uch as PDT,s hould overcome the medicinal challenge of side effects.However,the reality is that classical PSs have dark toxicity and al ack of selectivity, which causes undesirable adverse effects.Optogenetics [3] and photopharmacology [4] hold the promise to solve off-target issues,a lthough, unlike PDT,t hey are not yet at the stage of clinical development. Therefore,t here is ac lear need for improved PS designs that increase selectivity and minimize collateral injury to healthy tissue.A long these lines,s everal groups have demonstrated the potential of second-generation PSs,w hose therapeutic properties had been improved by either controllable activation [5] or specific delivery of the PSs. [6] Herein, we envision at hird-generation of PSs that combine both modulation of singlet oxygen ( 1 O 2 )production and controlled localization through ab ioorthogonal inverse-electron-demand Diels-Alder (iEDDA) tetrazine cycloaddition reaction.Since the discovery of the suitability of tetrazines for the bioorthoonal ligation pool in 2008, [7] this approach has become ap owerful bioconjugation method for imaging, [8] detection, [9] diagnostics, [10] and bioorthogonal release reactions. [11] However, its potential has not yet been exploited in PDT.Indeed, to the best of our knowledge,n one of the bioorthogonal reactions has ad irect application in the modulation of ROSproduction. Therefore,taking advantage of such ar eaction and inspired by the pioneering work of Weissleder and co-workers on superbright bioorthogonal boron dipyrromethene (BODIPY)/tetrazine turn-on probes, [12] we explore novel bioorthogonal turn-on probes for the controllable generation of 1 O 2 from the straightforward functionalization of the 4,4-difluoro-4-bora-3a,4a-diazas-indacene core. [13] BODIPY-based PSs have excellent photophysical properties, [14] and the quantum yield of their triplet excited state could be enhanced by the incorporation of ...
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.
Shine light on epigenetics: we describe how photoswitchable peptidomimetics modulate the activity of the MLLl enzyme affecting epigenetic states.
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