Harnessing Unexpected Reaction Pathways: Tetrazole-Amine Photoclick Cyclizations for Live-Cell Protein Cross-Linking

Building on the serendipitous finding by Zhang et al. (2024, JACS) that tetrazoles can undergo photoinduced cyclization with amines (not just alkenes or acids), this idea proposes to systematically explore and engineer this chemistry for live-cell protein cross-linking. While existing bioorthogonal reactions focus on ligation or cleavage, this new cyclization could enable the targeted and light-triggered formation of stable 1,2,4-triazole bridges between proteins, such as cross-linking specific lysines. This is distinct from classic "click" labeling (see Bertozzi, 2022; Carlson et al., 2018) as it allows for the creation of covalent protein-protein (or protein-DNA) networks under precise temporal and spatial control. Such tools could revolutionize studies of dynamic protein complexes, signal transduction, or even synthetic cell scaffolds. The unexpected mechanism offers a toolbox expansion and a new paradigm in live-cell chemical biology.

References:

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