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Light-activated tetrazines enable live-cell spatiotemporal control of bioorthogonal reactions

Luping Liu, Dongyang Zhang, Mai Johnson, Neal K. Devaraj
doi: https://doi.org/10.1101/2020.12.01.405423
Luping Liu
1Department of Chemistry and Biochemistry, University of California, San Diego, California 92093, United States
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Dongyang Zhang
1Department of Chemistry and Biochemistry, University of California, San Diego, California 92093, United States
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Mai Johnson
1Department of Chemistry and Biochemistry, University of California, San Diego, California 92093, United States
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Neal K. Devaraj
1Department of Chemistry and Biochemistry, University of California, San Diego, California 92093, United States
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  • For correspondence: ndevaraj@ucsd.edu
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Abstract

Bioorthogonal ligations encompass coupling chemistries that have considerable utility in living systems.1–3 Among the numerous bioorthogonal chemistries described to date, cycloaddition reactions between tetrazines and strained dienophiles are widely used in proteome, lipid, and glycan labeling due to their extremely rapid kinetics.4,5 In addition, a variety of functional groups can be released after the cycloaddition reaction,6,7 and drug delivery triggered by in vivo tetrazine ligation8 is in human phase I clinical trials.9 While applications of tetrazine ligations are growing in academia and industry, it has so far not been possible to control this chemistry to achieve the high degrees of spatial and temporal precision necessary for modifying mammalian cells with single-cell resolution. Here we demonstrate visible light-activated formation of tetrazines from photocaged dihydrotetrazines, which enables live-cell spatiotemporal control of rapid biorthogonal cycloaddition reactions between tetrazines and dienophiles such as trans-cyclooctenes (TCOs). Photocaged dihydrotetrazines are stable in conditions that normally degrade tetrazines, enabling efficient early-stage incorporation of bioorthogonal handles into biomolecules such as peptides. Photocaged dihydrotetrazines allow the use of non-toxic visible light to trigger tetrazine ligations on live mammalian cells. By tagging reactive phospholipids with fluorophores, we demonstrate modification of HeLa cell membranes with single-cell spatial resolution. Finally, we show that photo-triggered therapy is possible by coupling tetrazine photoactivation with strategies that uncage prodrugs in response to tetrazine ligation, opening up new methods for photopharmacology and precision drug delivery using bioorthogonal chemistry.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted December 02, 2020.
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Light-activated tetrazines enable live-cell spatiotemporal control of bioorthogonal reactions
Luping Liu, Dongyang Zhang, Mai Johnson, Neal K. Devaraj
bioRxiv 2020.12.01.405423; doi: https://doi.org/10.1101/2020.12.01.405423
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Light-activated tetrazines enable live-cell spatiotemporal control of bioorthogonal reactions
Luping Liu, Dongyang Zhang, Mai Johnson, Neal K. Devaraj
bioRxiv 2020.12.01.405423; doi: https://doi.org/10.1101/2020.12.01.405423

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