Paper
Synthesis and application of 3-bromo-1,2,4,5-tetrazine for protein labeling to trigger click-to-release biorthogonal reactions.
Published Feb 14, 2020 · Enric Ros, Marina Bellido, X. Verdaguer
Bioconjugate chemistry
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Abstract
3-Bromo-1,2,4,5-tetrazine has been synthetized in an oxidant- and metal-free method. The synthesis is scalable and relies on inexpensive starting materials. 3-bromo-1,2,4,5-tetrazine can undergo nucleophilic aromatic substitutions with differently substituted heteroatoms under mild conditions. In particular, its excellent reactivity has been used to attain chemoselective protein labeling. The resulting labeled lysines can react with strained dienophiles to trigger fast click-to-release (CtR) biorthogonal reactions. The characterization of the CtR reaction in physiological conditions and a therapeutically relevant example with the monoclonal antibody Trastuzumab to show-case its application is presented. Finally, 3-bromo-1,2,4,5-tetrazine has been used to achieve site-selective protein labeling through the genetic incorporation of the first unnatural amino acid bearing an unsubstituted 1,2,4,5-tetrazin-3-yl functionality, which can also undergo CtR reactions.
3-bromo-1,2,4,5-tetrazine enables chemoselective protein labeling, enabling fast click-to-release biorthogonal reactions in therapeutic applications.
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