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Bioorthogonal Chemistry

We aim for the development and further enhancement of bioorthogonal reactions in consideration of the most important requirements: (1) reactivity, (2) efficiency, (3) selectivity, (4) stability, and (5) biocompatibility.

We focus on a better understanding of the underlying mechanisms of bioorthogonal ligations and bond-cleavage reactions to develop new tools for various applications. Due to the favorable reaction kinetics of the click chemistry between tetrazines and trans-cyclooctenes, these compounds are omnipresent in our labs and almost not a single day goes by without seeing someone working with a pink colored solid or solution.

Click-to-release chemistry, as pioneered by one of our collaborators, Marc Robillard and coworkers (see here), is probably the most exciting reaction for us these days. In case of bioorthogonal bond-cleavage the requirements as mentioned above play an even more pivotal role. Sufficient reaction kinetics of both, ligation and elimination, and high efficiency (i.e. reaction yield) are essential criteria for successful application of click-to-release. Together with our colleagues in Boston (Jonathan Carlson and Ralph Weissleder; during Hannes' postdoc in the Weissleder Lab) we have recently unraveled crucial mechanisms of this reaction and shown how to exploit this knowledge to achieve ultrafast and efficient release, and finally introduced the 'release cube' as a schematic overview of the postclick reaction network (see here).

Radiolabeled bioorthogonal probes and tools

Another major focus of the group is the development of strategies and methods for the preparation of radiolabeled bioorthogonal tools, mainly tetrazines. In fact, the motivation to develop 18F-labeled tetrazines toward pretargeted PET imaging actually got us to the field of bioorthogonal chemistry. A few years ago we have been successful in developing the first 18F-tetrazine (see here) and since then we aim to design strategies to access highly reactive radiolabeled tetrazines for diagnostic and/or therapeutic application. As part of a European consortium we are currently working on advancing bioorthogonal strategies toward pretargeted PET imaging (HORIZON 2020 project 'Click-It', see here).
Based on improved methods for the synthesis of radiolabeled tetrazines, we have recently expanded our efforts toward other radionuclides with the aim to develop and investigate bioorthogonal radiotheranostic strategies (see here & here).
The favorable reaction kinetics of tetrazine ligations, moreover, make them exceptional tools for rapid radiolabeling. We currently aim to develop new enhanced methods for the radiolabeling of biomolecules to rapidly access radiotheranostic compounds. 

Development of diagnostic tools (in vitro assays)

Bioorthogonal or - more generally speaking - click reactions are highly valuable tools not only for in vivo, but also in vitro application. The copper-catalyzed alkyne-azide cycloaddition (as developed and termed 'click chemistry' by Sharpless and coworkers) represents a powerful tool to connect two different compounds/moieties with high selectivity and efficiency.
We have exploited the beneficial properties of click chemistry to design a building block strategy for rapid and modular assembly of enzyme substrates toward the newborn screening of rare diseases (see here). Based on this concept we focus on the development of new chemical tools and in vitro assays for diagnostic application (also including therapeutic drug monitoring).

Bioorthogonal targeting strategies

Based on our investigations in the field of bioorthogonal chemistry and radiotheranostics we more and more focus on the development of new strategies (i) to selectively deliver therapeutic radionuclides or activate (pro)drugs at the site of disease (e.g. inside tumor cells), (ii) to circumvent and/or resolve problems related to unspecific delivery of carrier molecules (e.g. nanomedicines) leading to off-target toxicity, and (iii) to cross biological barriers.