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Site-selective protein modification via disulfide rebridging for fast tetrazine/trans-cyclooctene bioconjugation

Abstract

The inverse electron demand Diels-Alder reaction between tetrazine and trans-cyclooctene (TCO) holds great promise in protein modification and manipulation. Herein, we report the design and synthesis of a tetrazine-based disulfide rebridging reagent, which allows the site-selective installation of a tetrazine group to disulfide-containing peptides and proteins such as the hormone somatostatin (SST) and the antigen binding fragment (Fab) of human immunoglobulin G (IgG). The fast and efficient conjugation of the tetrazine modified proteins with three different TCO-containing substrates to form a set of bioconjugates in a site-selective manner was successfully demonstrated for the first time. Homogeneous, well-defined bioconjugates were obtained underlining the great potential of our method for fast bioconjugation of emerging protein therapeutics. The formed bioconjugates were stable against glutathione and in serum and they maintained their secondary structure. With this work, we broaden the scope of tetrazine chemistry for the site-selective protein modification to prepare well-defined SST and Fab conjugates with preserved structure and good stability in biologically relevant conditions.

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Supplementary files

Article information


Submitted
18 Dec 2019
Accepted
08 Jan 2020
First published
09 Jan 2020

This article is Open Access

Org. Biomol. Chem., 2020, Accepted Manuscript
Article type
Paper

Site-selective protein modification via disulfide rebridging for fast tetrazine/trans-cyclooctene bioconjugation

L. Xu, M. Raabe, M. M. Zegota, J. Nogueira, V. Chudasama, S. L. Kuan and T. Weil, Org. Biomol. Chem., 2020, Accepted Manuscript , DOI: 10.1039/C9OB02687H

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