Chemoselective cysteine or disulfide modification via single atom substitution in chloromethyl acryl reagents. Issue 40 (17th September 2021)

• Record Type: Journal Article
• Authors: Xu, Lujuan; Silva, Maria J. S. A.; Gois, Pedro M. P.; Kuan, Seah Ling; Weil, Tanja
• Is Part Of: Chemical science. Volume 12:Issue 40(2021)
• Page Start: 13321
• Page End: 13330
• Publication Date: 2021-09-17
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d1sc03250j
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : 2-Chloromethyl acryl derivatives (acrylamides and acrylates) can serve as simple and versatile bioconjugation reagents to achieve site-selective cysteine and disulfide modification on demand and with high efficiency. 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.