Prof. H. Mikula: "Exit the Cube: Molecular Tools for Next-Level Bioorthogonal Bond-Cleavage"

Organisch-chemisches Kolloquium

The Institute of Organic Chemistry invites to the lecture of

Prof. Dr. Hannes Mikula, Technische Universität Wien

who will be talking about

 "Exit the Cube: Molecular Tools for Next-Level Bioorthogonal Bond-Cleavage"

Abstract:

Bioorthogonal chemistry is bridging the divide between static chemical connectivity and the dynamic physiologic regulation of molecular state, enabling transformations that drive multiple technologies. 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, the concept of bioorthogonal bond-cleavage has further expanded the repertoire of in vivo chemical methods, with the reactions of tetrazines and trans-cyclooctenes (TCO) standing out due to exceptional reaction kinetics and structural versatility. This emerging class of molecular transformations has enabled a variety of applications, including new concepts for drug delivery and activation, as well as methods to spatiotemporally control the function of molecules in biological environments. However, despite significant advances in the field, existing chemical tools have fundamentally lacked the performance characteristics (i.e., click kinetics, cleavage kinetics, cleavage yield) needed to make more advanced strategies plausible. Based on our rigorous pursuit of mechanistic understanding, we have developed molecular tools with exceptional chemical performance and unique capabilities. Our C2-symmetric TCO-linker (C2TCO) can be cleaved efficiently within minutes, which allowed us to introduce bioorthogonal turn-off as a new concept, for instance, to achieve multiplexed spatiotemporal immunofluorescence imaging of living cells and tissues. Based on these insights and the unexpected discovery of a new release mechanism, we have developed molecular tools, including tetrazine scissors and the click-cleavable linker iTCO, finally enabling us to perform next-level bioorthogonal bond-cleavage.