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Dichloro Butenediamides as Irreversible Site‐Selective Protein Conjugation Reagent

Published version
Peer-reviewed

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Authors

Laserna, Victor 
Abegg, Daniel 
Afonso, Cláudia F.  ORCID logo  https://orcid.org/0000-0003-4228-8834
Martin, Esther M. 
Adibekian, Alexander 

Abstract

Abstract: We describe maleic‐acid derivatives as robust cysteine‐selective reagents for protein labelling with comparable kinetics and superior stability relative to maleimides. Diamide and amido‐ester derivatives proved to be efficient protein‐labelling species with a common mechanism in which a spontaneous cyclization occurs upon addition to cysteine. Introduction of chlorine atoms in their structures triggers ring hydrolysis or further conjugation with adjacent residues, which results in conjugates that are completely resistant to retro‐Michael reactions in the presence of biological thiols and human plasma. By controlling the microenvironment of the reactive site, we can control selectivity towards the hydrolytic pathway, forming homogeneous conjugates. The method is applicable to several scaffolds and enables conjugation of different payloads. The synthetic accessibility of these reagents and the mild conditions required for fast and complete conjugation together with the superior stability of the conjugates make this strategy an important alternative to maleimides in bioconjugation.

Description

Keywords

Research Article, Research Articles, bioconjugation, cysteine, irreversibility, maleimides, Michael addition

Journal Title

Angewandte Chemie International Edition

Conference Name

Journal ISSN

1433-7851
1521-3773

Volume Title

Publisher

Sponsorship
fundação para a ciência e a tecnologia (PD/BD/135512/2018, CEECIND/00453/2018)
agencia estatal de investigación (RTI2018-099592-B-C21)
European Union's Horizon 2020 (836698, 852985)