生物正交化学
四嗪
化学
生物结合
环加成
点击化学
生物分子
聚糖
组合化学
生物物理学
生物化学
有机化学
糖蛋白
生物
催化作用
作者
Luping Liu,Dongyang Zhang,Mai Johnson,Neal K. Devaraj
出处
期刊:Nature Chemistry
[Springer Nature]
日期:2022-07-04
卷期号:14 (9): 1078-1085
被引量:44
标识
DOI:10.1038/s41557-022-00963-8
摘要
Bioorthogonal cycloaddition reactions between tetrazines and strained dienophiles are widely used for protein, lipid and glycan labelling because of their extremely rapid kinetics. However, controlling this chemistry in the presence of living mammalian cells with a high degree of spatial and temporal precision remains a challenge. Here we demonstrate a versatile approach to light-activated formation of tetrazines from photocaged dihydrotetrazines. Photouncaging, followed by spontaneous transformation to reactive tetrazine, enables live-cell spatiotemporal control of rapid bioorthogonal cycloaddition with dienophiles such as trans-cyclooctenes. 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 light to trigger tetrazine ligations on living 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 release prodrugs in response to tetrazine ligation. Developing stimuli-responsive bioorthogonal tetrazine ligations remains highly challenging, but a versatile approach that uses photocaged dihydrotetrazines has now been developed. Photouncaging results in the spontaneous formation of reactive tetrazines that rapidly react with dienophiles such as trans-cyclooctenes. As a demonstration, the method was used for live-cell labelling with single-cell precision and light-triggered drug delivery.
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