Next-Level Bioorthogonal Click-to-Release: Cleaving Molecules without Detours and Dead Ends

Tuesday 28 May 2024, 4 pm

The toolbox of bioorthogonal reactions has expanded substantially in the past decade, providing chemists with highly selective methods to achieve efficient ligation in complex biological environments, even in living systems. In parallel, bioorthogonal bond-cleavage has emerged as a new concept, 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 favorable reaction kinetics and adaptability. This click-triggered bond-cleavage reaction has enabled strategies for targeted drug delivery and prodrug activation, as currently tested in clinical trials, which marks the beginning of the era of clinical translation of bioorthogonal chemistry. 

To date, however, the concept of bioorthogonal Tz/TCO bond-cleavage has been limited, as existing tools have fundamentally lacked the performance characteristics (i.e., click kinetics, cleavage kinetics, cleavage yield) needed to make more advanced strategies plausible. For instance, efficient TCO-release has yet been restricted to tetrazines with relatively low click reactivity, while highly reactive tetrazines achieve only limited release (<10%). Based on our rigorous pursuit of mechanistic understanding, we have developed next-level bioorthogonal scissors and click-cleavable linkers with unique capabilities. In this lecture I will give an overview of our key molecular designs and summarize the challenges we faced on the way to boost Tz/TCO click-to-release, ultimately to enable bioorthogonal bond-cleavage with unprecedented kinetics and efficiency.

prof. Hannes Mikula
Tuesday 28 May 2024, 4 pm
Prof. Hannes Mikula, TU Wien, Austria
Huygens building, HG00.303