Unleashing the Power of Bond Cleavage Chemistry in Living Systems

Wang, Jie; Wang, Xin; Fan, Xinyuan; Chen, Peng R.

doi:10.1021/acscentsci.1c00124

Cited by 155 publications

(102 citation statements)

References 138 publications

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“…We started by developing the bioorthogonal decaging chemistry − with major considerations on modifiable catalysts for spatial targeting to mitochondria, external visible light for temporal regulation, and fast reaction kinetics for precise temporal control. The transformation of aryl azide to aniline was chosen as the model reaction due to its well-documented bioorthogonality, but further development of more suitable catalytic system is needed for expanding the utility of this reaction in living systems. − Therefore, 4-azidobenzoic acid ( 1 ) was subjected to a collection of photocatalysts (10 mol %), including ruthenium complexes, organic photosensitizers, and iridium complexes, under white LED irradiation in H 2 O/DMSO (1/1) with NADH as additive (Figures a and S1).…”

Section: Results and Discussionmentioning

confidence: 99%

Bioorthogonal Photocatalytic Decaging-Enabled Mitochondrial Proteomics

et al. 2021

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Spatiotemporally resolved dissection of subcellular proteome is crucial to our understanding of cellular functions in health and disease. We herein report a bioorthogonal and photocatalytic decaging-enabled proximity labeling strategy (CAT-Prox) for spatiotemporally resolved mitochondrial proteome profiling in living cells. Our systematic survey of the photocatalysts has led to the identification of Ir(ppy)2bpy as a bioorthogonal and mitochondria-targeting catalyst that allowed photocontrolled, rapid rescue of azidobenzyl-caged quinone methide as a highly reactive Michael acceptor for proximity-based protein labeling in mitochondria of live cells. Upon careful validation through in vitro labeling, mitochondria-targeting specificity, in situ catalytic activity as well as protein tagging, we applied CAT-Prox for mitochondria proteome profiling in living Hela cells as well as hard-to-transfect macrophage RAW264.7 cells with approximately 70% mitochondria specificity observed from up to 300 proteins enriched. Finally, CAT-Prox was further applied to the dynamic dissection of mitochondria proteome of macrophage cells upon lipopolysaccharide stimulation. By integrating photocatalytic decaging chemistry with proximity-based protein labeling, CAT-Prox offers a general, catalytic, and nongenetic alternative to the enzyme-based proximity labeling strategies for diverse live cell settings.

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Section: Results and Discussionmentioning

confidence: 99%

Bioorthogonal Photocatalytic Decaging-Enabled Mitochondrial Proteomics

et al. 2021

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“…to unleash the active drug payload, and has been demonstrated to be very successful to address some critical drug developability issues, including optimizing physiochemical and pharmacokinetic profiles and minimizing off-target toxicities, among others. [1] In recent years, bond cleavage triggered by exogenous stimuli such as light, [2] X-ray, [3] mechanical force, [4] and chemical [5,6] has emerged as an extraordinarily promising strategy for "on-demand" prodrug activation. Among these exogenous stimuli, photoirradiation is the most well-developed and frequently used to achieve localized drug delivery.…”

Section: Introductionmentioning

confidence: 99%

Chemiexcitation‐Triggered Prodrug Activation for Targeted Carbon Monoxide Delivery

Min

Meng

et al. 2022

Angew Chem Int Ed

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Photolysis-based prodrug strategy can address some critical drug delivery issues, which otherwise are very challenging to tackle with traditional prodrug strategy. However, the need for external light irradiation significantly hampers its in vivo application due to the poor light accessibility of deep tissue. Herein, we propose a new strategy of chemiexcitation-triggered prodrug activation, wherein a photoresponsive prodrug is excited for drug payload release by chemiexcitation instead of photoirradiation. As such, the bond-cleavage power of photolysis can be employed to address some critical drug delivery issues while obviating the need for external light irradiation. We have established the proof of concept by the successful development of a chemiexcitation responsive carbon monoxide delivery platform, which exhibited specific CO release at the tumor site and pronounced tumor suppression effects. We anticipate that such a concept of chemiexcitationtriggered prodrug activation can be leveraged for the targeted delivery of other small molecule-based drug payloads.

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“…However, molecular design principles accommodating both stability and cleavability for protein conjugates are still limited. Much of the bond cleavage chemistry is not compatible with mild, near-physiological conditions (neutral pH at ambient temperature in aqueous media) and functional group-enriched circumstances. − …”

Section: Introductionmentioning

confidence: 99%

Protein Modification at Tyrosine with Iminoxyl Radicals

et al. 2021

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Post-translational modifications (PTMs) of proteins are a biological mechanism for reversibly controlling protein function. Synthetic protein modifications (SPMs) at specific canonical amino acids can mimic PTMs. However, reversible SPMs at hydrophobic amino acid residues in proteins are especially limited. Here we report a tyrosine (Tyr)-selective SPM utilizing persistent iminoxyl radicals, which are readily generated from sterically hindered oximes via single electron oxidation. The reactivity of iminoxyl radicals with Tyr was dependent on the steric and electronic demands of oximes; isopropyl methyl piperidinium oxime 1f formed stable adducts, whereas the reaction of tert-butyl methyl piperidinium oxime 1o was reversible. The difference in reversibility between 1f and 1o, differentiated only by one methyl group, is due to the stability of iminoxyl radicals, which is partly dictated by the bond dissociation energy of oxime O-H groups. The Tyr-selective modifications with 1f and 1o proceeded under physiologicallyrelevant, mild conditions. Specifically, the stable Tyr-modification with 1f introduced functional small molecules, including an azobenzene photoswitch, to proteins, whereas the reversible modification of Tyr with 1o switched protein function on and off in an enzyme and in a monoclonal antibody by modification and deconjugation processes. ASSOCIATED CONTENTSupporting Information. Experimental procedures, characterization data, computational procedure, and data. The Supporting Information is available free of charge at https://pubs.acs.org.

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Unleashing the Power of Bond Cleavage Chemistry in Living Systems

Cited by 155 publications

References 138 publications

Bioorthogonal Photocatalytic Decaging-Enabled Mitochondrial Proteomics

Bioorthogonal Photocatalytic Decaging-Enabled Mitochondrial Proteomics

Chemiexcitation‐Triggered Prodrug Activation for Targeted Carbon Monoxide Delivery

Protein Modification at Tyrosine with Iminoxyl Radicals

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