Bringing Orthogonality in the Tetrazine Ligation with (strained) alkenes

The development of bioorthogonal reactions made it possible to visualize and study biomolecules in their native cellular context and contributed to advanced targeted drug delivery strategies. Bonger's research group is interested in developing novel bioorthogonal chemistry and apply this in the targeting of specific cell types. They recently added non-strained, highly soluble and stable vinylboronic acids (VBA) as reactants to the bioorthogonal toolbox which react with tetrazines in an inverse-electron demand Diels-Alder reaction. They have observed exceptional high reaction rates between non-strained vinylboronic acids (VBAs) and dipyridyl tetrazines relative to that of tetrazines lacking such dative coordinating ligand. As VBAs are mild Lewis acids, they hypothesize that coordination of the pyridyl to the boronic acid promotes the tetrazine ligation. In the current presentation, they explore the scope and molecular origins of the observed VBA reactivity in more detail and benefit from its unique properties in the simultaneous orthogonal tetrazine labelling of proteins. In addition, they further extended the VBA toolbox as chemically-triggered cleavable linkers for targeted drug delivery with the specific focus on autoreactive B-cells.
 
References:
1) Selma Eising, Francis Lelivelt, Kimberly M. Bonger*. Vinylboronic Acids as Fast Reacting, Synthetically Accessible, and Stable Bioorthogonal Reactants in the Carboni–Lindsey Reaction. Angew. Chem. Int. Ed. 2016, 55, 12243.
2) Selma Eising, Nicole van der Linden, Fleur Kleinpenning, Kimberly M. Bonger. Vinylboronic Acids as Efficient Bioorthogonal Reactants for Tetrazine Labeling in Living Cells. Bioconjug. Chem. 2018, 29, 982.
3) Selma Eising, Bo-Tao Xin, Fleur Kleinpenning, Jurriaan J. A. Heming, Bogdan I. Florea, Herman S. Overkleeft and Kimberly M. Bonger* Coordination-Assisted Bioorthogonal Chemistry: Orthogonal Tetrazine Ligation with Vinylboronic Acid and a Strained Alkene, ChemBioChem 2018, 15, 1648.

Biosketch :
Kimberly Bonger obtained her M.Sc degree in Organic Chemistry from the Free University in Amsterdam in 2002. In 2008 she received her PhD from Leiden University working under the supervision of Prof. Dr. Gijs van der Marel and Prof. Dr. Hermen Overkleeft on the design and synthesis of dimeric ligands for G-protein coupled receptors involved in human reproduction. After spending almost four years as a postdoc at Stanford University in the laboratory of Thomas Wandless working on molecular tools to control protein stability, she returned to the Netherlands as an assistant professor in Chemical Biology at the Radboud University in Nijmegen. Her research focusses on the development of novel bioorthogonal reactions and targeted drug delivery strategies as well as the fundamental understanding of cellular mechanisms involved in autoimmunity.