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Turning on bioorthogonal reactions catalytically

Catalysts could help researchers control when and where tetrazine ligations occur in cells or organisms

by Stu Borman
April 29, 2016 | A version of this story appeared in Volume 94, Issue 18

Reaction scheme shows how an enzyme or photocatalyst converts unreactive dihydrotetrazine to reaction-ready tetrazine.

To attach probes for imaging to biomolecules inside cells or organisms, chemists have developed so-called bioorthogonal reactions that don’t interfere with the biochemistry of the living things. Tetrazine ligation is the fastest of these bioorthogonal reactions, and its speed allows scientists to use small amounts of reagents to get the job done.

A new catalytic form of this ligation could enable researchers to control the timing and location of the reaction inside cells or organisms by turning on the chemistry with either an enzyme or a pulse of light.

Early bioorthogonal reactions were slow, so scientists had to introduce reagents at undesirably high concentrations to ensure the compounds could react before being cleared away by metabolic processes.

Researchers developed faster reactions so they could use reagents at lower concentrations. Tetrazine ligation, which is now used widely in bioorthogonal chemistry, involves the cycloaddition of tetrazine with a trans-cyclooctene or another strained alkene conjugated with a biomolecule.

Joseph Fox and his coworkers at the University of Delaware helped develop tetrazine ligation and have now enhanced the technique by finding ways to turn it on catalytically (J. Am. Chem. Soc. 2016, DOI: 10.1021/jacs.6b02168). The scientists use an enzyme or a near-infrared light-induced photocatalyst, methylene blue, to convert unreactive dihydrotetrazine to reaction-ready tetrazine (shown). Researchers have used ultraviolet light to activate bioorthogonal reactions before, but near-IR radiation is less damaging to tissue and penetrates more deeply than UV, about 0.6 cm.

“Numerous colleagues have asked me if there are good ways to use light to spatiotemporally control tetrazine ligations,” and now there is, comments Neal Devaraj of the University of California, San Diego, another developer of the tetrazine ligation technique.

“This is an exciting development,” says bioorthogonal chemistry specialist Qing Lin of the University at Buffalo, SUNY. “Potential applications include cell imaging, prodrug activation, and tissue engineering.”



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