Modular activatable bioorthogonal reagents

Kumar, Pratik; Laughlin, Scott T.

doi:10.1016/bs.mie.2019.02.007

Cited by 11 publications

(8 citation statements)

References 109 publications

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“…Although significant effort has been devoted to developing newer, − faster, − and mutually orthogonal bioorthogonal reagents, − only a limited subset allow for activation of their bioorthogonal reactivities . Activatable bioorthogonal reagents are initially unreactive to their bioorthogonal reaction partner, but upon activation by an external stimulus (e.g., light or an enzyme), they generate a reactive bioorthogonal reagent, providing control over their bioorthogonal reactivity.…”

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confidence: 99%

Caged Cyclopropenes with Improved Tetrazine Ligation Kinetics

et al. 2019

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Activatable cyclopropenes are unreactive toward their inverse electron demand Diels–Alder reaction partner (e.g., s-tetrazines) until they are activated. The activation strategy is highly modular due to the cyclopropene’s ability to be caged by various light- and enzyme-activatable groups. This work describes the next generation of activatable cyclopropenes with a new core scaffold that maintains the activation modularity of the first generation but improves upon the ligation kinetics with s-tetrazines by ≤270-fold.

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confidence: 99%

Caged Cyclopropenes with Improved Tetrazine Ligation Kinetics

et al. 2019

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“…With tetrazine‐modified proteins at hand, we set out to develop photochemically triggered iEDDAC (photo‐iEDDAC) that confers temporal and spatial control to the labeling of target proteins . To achieve this goal we explored the photochemical generation of reactive BCN‐probes.…”

Section: Resultsmentioning

confidence: 99%

Photo‐induced and Rapid Labeling of Tetrazine‐Bearing Proteins via Cyclopropenone‐Caged Bicyclononynes

et al. 2019

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Inverse electron-demand Diels-Alder cycloadditions (iEDDAC)b etween tetrazines and strained alkenes/ alkynes have emerged as essential tools for studying and manipulating biomolecules.Alight-triggered version of iED-DAC( photo-iEDDAC)i sp resented that confers spatiotemporal control to bioorthogonal labeling in vitro and in cellulo.Acyclopropenone-caged dibenzoannulated bicyclo-[6.1.0]nonyne probe (photo-DMBO) was designed that is unreactive towards tetrazines before light-activation, but engages in iEDDAC after irradiation at 365 nm. Aminoacyl tRNAsynthetase/tRNApairs were discovered for efficient sitespecific incorporation of tetrazine-containing amino acids into proteins in living cells.Insitu light activation of photo-DMBO conjugates allows labeling of tetrazine-modified proteins in living E. coli. This allows proteins in living cells to be modified in aspatio-temporally controlled manner and may be extended to photo-induced and site-specific protein labeling in animals.

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“…More recently, chemists have designed reactions with an eye towards expanded capabilities, including click-and-release for on-demand drug delivery 3 and the ability to be “turned on” by exposure to an external stimulus ( e . g ., light, enzyme, or metabolites) 4–6 . These activatable bioorthogonal reactions provide the means to control when and where the reaction occurs, promising the ability to limit bioorthogonal reactions to specific cell types or subcellular locations, an incredibly useful feature that has been available to protein-based tools for decades.…”

Section: Introductionmentioning

confidence: 99%

Redox Activated Substrates for Enhancing Activatable Cyclopropene Bioorthogonal Reactions

Kao,

Huang,

Zhang

et al. 2023

Preprint

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Bioorthogonal chemistry has become a mainstay in chemical biology and is making inroads in the clinic with recent advances in protein targeting and drug release. Since the field’s beginning, a major focus has been on designing bioorthogonal reagents with good selectivity, reactivity, and stability in complex biological environments. More recently, chemists have imbued reagents with new functionalities like click-and-release or light/enzyme-controllable reactivity. We have previously developed a controllable cyclopropene-based bioorthogonal ligation, which has excellent stability in physiological conditions and can be triggered to react with tetrazines by exposure to enzymes, biologically significant small molecules, or light spanning the visual spectrum. Here, to improve reactivity and gain a better understanding of this system, we screened diene reaction partners for the cyclopropene. We found that a cyclopropene–quinone pair is 26 times faster than reactions with 1,2,4,5-tetrazines. Additionally, we showed that the reaction of the cyclopropene–quinone pair can be activated by two orthogonal mechanisms, caging group removal on the cyclopropene and oxidation/reduction of the quinone. Finally, we demonstrated that this caged cyclopropene–quinone can be used as a bioorthogonal imaging tool to label the membranes of cultured cells.

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Modular activatable bioorthogonal reagents

Cited by 11 publications

References 109 publications

Caged Cyclopropenes with Improved Tetrazine Ligation Kinetics

Caged Cyclopropenes with Improved Tetrazine Ligation Kinetics

Photo‐induced and Rapid Labeling of Tetrazine‐Bearing Proteins via Cyclopropenone‐Caged Bicyclononynes

Redox Activated Substrates for Enhancing Activatable Cyclopropene Bioorthogonal Reactions

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