Issue 40, 2021

Chemoselective cysteine or disulfide modification via single atom substitution in chloromethyl acryl reagents

Abstract

The development of bioconjugation chemistry has enabled the combination of various synthetic functionalities to proteins, giving rise to new classes of protein conjugates with functions well beyond what Nature can provide. Despite the progress in bioconjugation chemistry, there are no reagents developed to date where the reactivity can be tuned in a user-defined fashion to address different amino acid residues in proteins. Here, we report that 2-chloromethyl acryl reagents can serve as a simple yet versatile platform for selective protein modification at cysteine or disulfide sites by tuning their inherent electronic properties through the amide or ester linkage. Specifically, the 2-chloromethyl derivatives (acrylamide or acrylate) can be obtained via a simple and easily implemented one-pot reaction based on the coupling reaction between commercially available starting materials with different end-group functionalities (amino group or hydroxyl group). 2-Chloromethyl acrylamide reagents with an amide linkage favor selective modification at the cysteine site with fast reaction kinetics and near quantitative conversations. In contrast, 2-chloromethyl acrylate reagents bearing an ester linkage can undergo two successive Michael reactions, allowing the selective modification of disulfides bonds with high labeling efficiency and good conjugate stability.

Graphical abstract: Chemoselective cysteine or disulfide modification via single atom substitution in chloromethyl acryl reagents

Supplementary files

Article information

Article type
Edge Article
Submitted
15 Jūn. 2021
Accepted
06 Sept. 2021
First published
09 Sept. 2021
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2021,12, 13321-13330

Chemoselective cysteine or disulfide modification via single atom substitution in chloromethyl acryl reagents

L. Xu, M. J. S. A. Silva, P. M. P. Gois, S. L. Kuan and T. Weil, Chem. Sci., 2021, 12, 13321 DOI: 10.1039/D1SC03250J

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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