Next-Level Bioorthogonal Bond-Cleavage Through Intramolecular Control of Click-To-Release Chemistry

Le résumé fourni par la source

Bioorthogonal bond-cleavage reactions are powerful tools for investigating biological dynamics and advancing therapeutic strategies. Primed by click reactivity, the multi-step cascades that lead to bioorthogonal release have nevertheless been challenging to navigate. For the widely recognized tetrazine-triggered cleavage of trans-cyclooctenes (TCO), the complexities of post-click tautomerization are the key barrier to achieving next-level molecular tools. Strategies to anchor directing functionalities to tetrazines (Tz) accelerate tautomerization, but their scope has been limited by interlocking impacts on Tz click reactivity and stability. Here we shift the tautomerization driving force from the Tz to the TCO, introducing iTCO, a click-cleavable linker that unlocks remarkably efficient release with highly reactive tetrazines, regardless of click orientation. Across biological systems of rising complexity—from media to in vivo—iTCO enables fast and complete click-triggered cleavage at single-digit micromolar concentrations in seconds, driving release performance to levels of bioorthogonal efficiency previously achieved only in ligations.

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