A mild TCEP-based para-azidobenzyl cleavage strategy to transform reversible cysteine thiol labelling reagents into irreversible conjugates

Maruani, Antoine; Alom, Shamim; Canavelli, Pierre; Lee, Maximillian T. W.; Morgan, Rachel; Chudasama, Vijay; Caddick, Stephen

doi:10.1039/c4cc08515a

Cited by 43 publications

(36 citation statements)

References 30 publications

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“…Irreversible cysteine modification using dibromo‐1,2‐dihydro‐pyridazine‐3,6‐diones was made possible by using p ‐azidobenzyl as a N ‐protection group such as in 111 . This feature allowed post‐conjugative TCEP‐mediated N ‐deprotection, yielding a thiol resistant N ‐unsubstituted adduct (Scheme ) …”

Section: Other Chemical Approaches For Maleimide‐like Bioconjugationmentioning

confidence: 99%

“…The DBPD platform has been considerably explored in the generation of ADCs, antibody conjugates, antibody directed photosensitizers, protein‐protein conjugates and targeted nanotherapeutics . A DBPD reagent incorporating a terminal alkyne and cyclooctyne probe was used to accomplish complete rebridging of Trastuzumab (4:1 ratio of PD‐to‐antibody).…”

Section: Other Chemical Approaches For Maleimide‐like Bioconjugationmentioning

confidence: 99%

“…Irreversible cysteine modification using dibromo-1,2-dihydro-pyridazine-3,6-diones was made possible by using p-azidobenzyl as a N-protection group such as in 111.T his feature allowed post-conjugative TCEPmediated N-deprotection, yielding at hiol resistant N-unsubstituted adduct (Scheme 24). [84] The DBPD platform has been considerably explored in the generation of ADCs, [85] antibody conjugates, [19,86,87] antibody directed photosensitizers, [84,88] protein-protein conjugates [89] and targeted nanotherapeutics. [90] AD BPD reagent incorporating a terminal alkyne and cyclooctyne probe was used to accomplish complete rebridging of Trastuzumab (4:1 ratio of PD-to-antibody).…”

Section: -Methylene Pyrrolonesmentioning

confidence: 99%

See 2 more Smart Citations

Bioconjugation with Maleimides: A Useful Tool for Chemical Biology

Ravasco

Faustino

Trindade

et al. 2018

Chemistry A European J

395

347

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Maleimide chemistry stands out in the bioconjugation toolbox by virtue of its synthetic accessibility, excellent reactivity, and practicability. The second-generation of clinically approved antibody-drug conjugates (ADC) and much of the current ADC pipeline in clinical trials contain the maleimide linkage. However, thiosuccinimide linkages are now known to be less robust than once thought, and ergo, are correlated with suboptimal pharmacodynamics, pharmacokinetics, and safety profiles in some ADC constructs. Rational design of novel generations of maleimides and maleimide-type reagents have been reported to address the shortcomings of classical maleimides, allowing for the formation of robust bioconjugate linkages. This review highlights the main strategies for rational reagent design that have allowed irreversible bioconjugations in cysteines, reversible labelling strategies and disulfide re-bridging.

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Section: Other Chemical Approaches For Maleimide‐like Bioconjugationmentioning

confidence: 99%

Section: Other Chemical Approaches For Maleimide‐like Bioconjugationmentioning

confidence: 99%

Section: -Methylene Pyrrolonesmentioning

confidence: 99%

See 1 more Smart Citation

Bioconjugation with Maleimides: A Useful Tool for Chemical Biology

Ravasco

Faustino

Trindade

et al. 2018

Chemistry A European J

395

347

View full text Add to dashboard Cite

show abstract

“…A further development of this work involves a strategy for rendering the conjugates resistant to thiol exchange . On the basis of the previous observation that reagents with unsubstituted nitrogen atoms within the ring were not reactive at higher than physiological pH, Maruani et al.…”

Section: Maleimidesmentioning

confidence: 99%

Chemical Protein Modification through Cysteine

2016

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The modification of proteins with non-protein entities is important for a wealth of applications, and methods for chemically modifying proteins attract considerable attention. Generally, modification is desired at a single site to maintain homogeneity and to minimise loss of function. Though protein modification can be achieved by targeting some natural amino acid side chains, this often leads to ill-defined and randomly modified proteins. Amongst the natural amino acids, cysteine combines advantageous properties contributing to its suitability for site-selective modification, including a unique nucleophilicity, and a low natural abundance--both allowing chemo- and regioselectivity. Native cysteine residues can be targeted, or Cys can be introduced at a desired site in a protein by means of reliable genetic engineering techniques. This review on chemical protein modification through cysteine should appeal to those interested in modifying proteins for a range of applications.

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“…In proteins, disulfide bonds are more common than free cysteines, and disulfide reduction followed by rebridging bioconjugation offers another approach for chemoselective modification of proteins and is especially attractive for functionalization of immunoglobulin G (IgG), an antibody that has four reducible interchain disulfides but no free cysteine [25][26][27][28] . Many reagents, including bromomaleimides 29,30 , bromopyridazinediones 27,[31][32][33] , bis-sulfones and allyl sulfones 24,26,34 , and divinylpyrimidine 28 , have been developed for such applications. Nevertheless, seldom of them meet the requirements of simplicity, robustness, and high efficiency.…”

mentioning

confidence: 99%

Cysteine-specific protein multi-functionalization and disulfide bridging using 3-bromo-5-methylene pyrrolones

Zhang

Zang

et al. 2020

Nat Commun

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Many reagents have been developed for cysteine-specific protein modification. However, few of them allow for multi-functionalization of a single Cys residue and disulfide bridging bioconjugation. Herein, we report 3-bromo-5-methylene pyrrolones (3Br-5MPs) as a simple, robust, and versatile class of reagents for cysteine-specific protein modification. These compounds can be facilely synthesized via a one-pot mild reaction and they show comparable tagging efficiency but higher cysteine specificity than the maleimide counterparts. The addition of cysteine to 3Br-5MPs generates conjugates that are amenable to secondary addition by another thiol or cysteine, making 3Br-5MPs valuable for multi-functionalization of a single cysteine and disulfide bridging bioconjugation. The labeling reaction and subsequent treatments are mild enough to produce stable and active protein conjugates for biological applications.

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A mild TCEP-based para-azidobenzyl cleavage strategy to transform reversible cysteine thiol labelling reagents into irreversible conjugates

Cited by 43 publications

References 30 publications

Bioconjugation with Maleimides: A Useful Tool for Chemical Biology

Bioconjugation with Maleimides: A Useful Tool for Chemical Biology

Chemical Protein Modification through Cysteine

Cysteine-specific protein multi-functionalization and disulfide bridging using 3-bromo-5-methylene pyrrolones

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