Chemoselective cysteine or disulfide modification <i>via</i> single atom substitution in chloromethyl acryl reagents

Xu, Lujuan; Silva, Maria J. S. A.; Góis, Pedro M. P.; Kuan, Seah Ling; Weil, Tanja

doi:10.1039/d1sc03250j

Cited by 18 publications

(12 citation statements)

References 45 publications

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“…A plethora of exciting reagents and technologies exist that can facilitate the selective modification of cysteine residues and disulfide bonds, each displaying a unique set of properties and associated advantages and disadvantages. [13][14][15][16][17][18][19][20][21] Amongst some of the most popular highly reactive cysteine-targeting technologies (e.g. maleimide and maleimide derivatives) issues can arise with regard to bioconjugate stability (i.e.…”

Section: Introductionmentioning

confidence: 99%

The use of bromopyridazinedione derivatives in chemical biology

Bahou¹,

Chudasama²

2022

Org. Biomol. Chem.

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Section: Introductionmentioning

confidence: 99%

The use of bromopyridazinedione derivatives in chemical biology

Bahou¹,

Chudasama²

2022

Org. Biomol. Chem.

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“…Disulfide rebridging of goat anti‐human IgG Fab fragment was achieved using this efficient 3Br‐5MP chemistry. Other activated Michael acceptors are also developed for rapid cysteine‐specific conjugation, such as 2‐chloromethyl acrylamide or acrylate, [25] and 4‐substituted cyclopentenone reagent [26] . 4‐Substituted cyclopentenone reagent 15 a was designed as the predecessor for unstable and antiaromatic cyclopentadienone 15 b , which reacts rapidly with cysteine with a rate constant of 100 M −1 s −1 at the peptide level (Figure 5C, equation 2).…”

Section: Introductionmentioning

confidence: 99%

Fast Cysteine Bioconjugation Chemistry

Chen

Gao

2022

Chemistry A European J

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Cysteine bioconjugation serves as a powerful tool in biological research and has been widely used for chemical modification of proteins, constructing antibody-drug conjugates, and enabling cell imaging studies. Cysteine conjugation reactions with fast kinetics and exquisite selectivity have been under heavy pursuit as they would allow clean protein modification with just stoichiometric amounts of reagents, which minimizes side reactions, simplifies purification and broadens functional group tolerance. In this concept, we summarize the recent advances in fast cysteine bioconjugation, and discuss the mechanism and chemical principles that underlie the high efficiencies of the newly developed cysteine reactive reagents.

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“…However, a systematic effort in the past few years to understand the principles for simultaneous regulation of reactivity and selectivity has rendered exciting insights. In this perspective, we and others demonstrated that methods could be designed to precisely target the reactivity hotspots in a protein. − Later, N-Cys − and N-Gly − targeting in a residue-specific process established the potential of multistep pathways. These transformations initiate through a reversible generation of imine.…”

Section: Introductionmentioning

confidence: 99%

Human Behavior-Inspired Linchpin-Directed Catalysis for Traceless Precision Labeling of Lysine in Native Proteins

et al. 2022

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The complex social ecosystem regulates the spectrum of human behavior. However, it becomes relatively easier to understand if we disintegrate the contributing factors, such as locality and interacting partners. Interestingly, it draws remarkable similarity with the behavior of a residue placed in a social setup of functional groups in a protein. Can it inspire principles for creating a unique environment for the precision engineering of proteins? We demonstrate that localization-regulated interacting partner(s) could render precise and traceless single-site modification of structurally diverse native proteins. The method targets a combination of high-frequency Lys residues through an array of reversible and irreversible reactions. However, excellent simultaneous control over chemoselectivity, site selectivity, and modularity ensures that the user-friendly protocol renders acyl group installation, including post-translational modifications (PTMs), on a single Lys. Besides, it offers a chemically orthogonal handle for the installation of probes. Also, a purification protocol integration delivers analytically pure single-site tagged protein bioconjugates. The precise labeling of a surface Lys residue ensures that the structure and enzymatic activities remain conserved post-bioconjugation. For example, the precise modification of insulin does not affect its uptake and downstream signaling pathway. Further, the method enables the synthesis of homogeneous antibody–fluorophore and antibody–drug conjugates (AFC and ADC; K183 and K249 labeling). The trastuzumab–rhodamine B conjugate displays excellent serum stability along with antigen-specific cellular imaging. Further, the trastuzumab–emtansine conjugate offers highly specific antiproliferative activity toward HER-2 positive SKBR-3 breast cancer cells. This work validates that disintegrate theory can create a comprehensive platform to enrich the chemical toolbox to meet the technological demands at the chemistry, biology, and medicine interface.

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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...

Cited by 18 publications

References 45 publications

The use of bromopyridazinedione derivatives in chemical biology

The use of bromopyridazinedione derivatives in chemical biology

Fast Cysteine Bioconjugation Chemistry

Human Behavior-Inspired Linchpin-Directed Catalysis for Traceless Precision Labeling of Lysine in Native Proteins

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