Unlocking Chemistry: Pushing the Limits of Bioorthogonal Click-To-Release

Bioorthogonal chemistry provides powerful tools for selective ligation and bond-cleavage in complex biological environments. Among these, the tetrazine/trans-cyclooctene (Tz/TCO) click-to-release reaction enables controlled molecular disassembly, advancing targeted drug delivery and prodrug activation, with first clinical trials now underway. However, conventional Tz/TCO systems suffered from incomplete or slow click-to-release.¹ We developed next-level molecular tools with exceptional kinetics and precision: a C₂-symmetric TCO (C₂TCO) that enables near-instantaneous cleavage,² hydroxypyridyl-tetrazines that achieve complete and accelerated release,³ and the intramolecularly controlled iTCO that allows highly reactive tetrazines to function as efficient molecular scissors, elevating click-to-release chemistry to the performance level required for efficient in vivo application.⁴ Together, these tools enable fast and near-quantitative bond-cleavage and cascade reactions with molecular precision for bioorthogonal ON/OFF control. This presentation will highlight the molecular designs and mechanistic insights that led us to redefine the performance limits of Tz/TCO click-to-release chemistry.

References
[1] Keppel P.; Hecko S.; Mikula H., Top. Curr. Chem. 2025, 383, 25.
[2] Wilkovitsch M.; Haider M.; Sohr B.; Herrmann B.; Klubnick J.; Weissleder R.; Carlson J. C. T.; Mikula H., J. Am. Chem. Soc. 2020, 142, 19132-19141.
[3] Wilkovitsch M.; Kuba W.; Keppel P.; Sohr B.; Löffler A.; Kronister S.; Fernandez del Castillo A.; Goldeck M.; Dzijak R.; Rahm M.; Vrabel M.; Svatunek D.; Carlson J. C. T.; Mikula H., Angew. Chem. Int. Ed. 2025, 64, e202411707.
[4] Kuba W.; Schiefer A.; Löffler A.; Houszka N.; Schnöll S.; Staudt M.; Demuth T.; Sohr B.; Haider M.; Kohler R.; Weissleder R.; Svatunek D.; Carlson J. C. T.; Mikula H., ChemRxiv 2025, DOI: 10.26434/chemrxiv-2025-7s39f.