The Department of Organic Chemistry kindly invites to the OC Seminar:

Univ.-Prof. Dipl.-Ing. Dr.techn. Hannes Mikula, TU Wien, Austria

“Unlocking Chemistry: Next-Level Bioorthogonal Click-to-Release”

The toolbox of bioorthogonal reactions has expanded substantially over the past decade, offering highly selective methods for efficient ligation in complex biological environments, even in living systems. In parallel, bioorthogonal bond-cleavage has emerged as a new modality, enabling controlled molecular disassembly under physiological conditions. Among these chemistries, the 'click-to-release' reaction of tetrazines (Tz) and cleavable trans-cyclooctenes (TCO) stands out due to its favorable kinetics and adaptability. This click-triggered bond-cleavage reaction has driven advances in targeted drug delivery and prodrug activation, leading to the first bioorthogonal approaches tested in clinical trials – a milestone in the clinical translation of in vivo chemistry. Despite these successes, bioorthogonal Tz/TCO bond-cleavage has faced several limitations, as existing molecular tools have fundamentally lacked the performance characteristics needed to make more advanced strategies feasible. For instance, efficient bioorthogonal cleavage has so far been restricted to tetrazines with relatively low click reactivity, while highly reactive tetrazine scaffolds achieve only minimal release. Guided by our rigorous pursuit of mechanistic understanding, we have developed next-level bioorthogonal scissors and click-cleavable linkers with unique capabilities. This presentation will highlight our key molecular designs and the challenges overcome to boost Tz/TCO click-to-release, ultimately ‘unlocking chemistry' to enable bioorthogonal ON/OFF control with unmatched kinetics and efficiency.