Journal
CHEMICAL SCIENCE
Volume 12, Issue 40, Pages 13321-13330Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/d1sc03250j
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Funding
- Max Planck Society
- Deutsche Forschungsgemeinscha. (DFG, German Research Foundation) [316249678-SFB 1279]
- China Scholarship Council
- Fundacao para a Ciencia e a Tecnologia, Ministerio da Ciencia e da Tecnologia, Portugal [SFRH/BD/132710/2017, iMed.ULisboa UIDB/04138/2020, UIDP/04138/2020, PTDC/QUI-QOR/29967/2017, LISBOA-010145-FEDER-029967]
- Fundação para a Ciência e a Tecnologia [PTDC/QUI-QOR/29967/2017, SFRH/BD/132710/2017] Funding Source: FCT
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The development of bioconjugation chemistry has created new classes of protein conjugates with functions beyond what Nature can provide, but there is still a lack of reagents that can tune reactivity to different amino acid residues. By modifying 2-chloromethyl acryl reagents, selective protein modification at cysteine or disulfide sites can be achieved.
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.
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