N-Terminal selective modification of peptides and proteins using 2-ethynylbenzaldehydes

Deng, Jie‐Ren; Lai, Nathanael Chun Him; Kung, Karen Ka‐Yan; Yang, Bin; Chung, Sai Fung; Leung, Alan Siu Lun; Choi, Man Chung; Leung, Yun Chung; Wong, Man Leung

doi:10.1038/s42004-020-0309-y

Cited by 34 publications

(16 citation statements)

References 37 publications

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“…25). 47 Exhibiting high lysine selectivity (81%) and good proteomic coverage (3796 quantified lysines, Fig. 4b, Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Profiling the Proteome-Wide Selectivity of Diverse Electrophiles

Zanon¹,

Yu²,

Zhang³

et al. 2021

Preprint

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<p><a>Targeted covalent inhibitors are powerful entities in drug discovery, but their application has so far mainly been limited to addressing cysteine residues. The development of cysteine-directed covalent inhibitors has largely profited from determining their proteome-wide selectivity using competitive residue-specific proteomics. Several probes have recently been described to monitor other amino acids using this technology and many more electrophiles exist to modify proteins. Nevertheless, a direct, proteome‑wide comparison of the selectivity of diverse probes is still entirely missing. Here, we developed a completely unbiased workflow to analyse electrophile selectivity proteome‑wide and applied it to directly compare 54 alkyne probes containing diverse reactive groups. In this way, we verified and newly identified probes to monitor a total of nine different amino acids as well as the <i>N</i>‑terminus proteome‑wide. This selection includes the first probes to globally monitor tryptophans, histidines and arginines as well as novel tailored probes for methionines, aspartates and glutamates.</a></p>

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“…25). 47 Exhibiting high lysine selectivity (81%) and good proteomic coverage (3796 quantified lysines, Fig. 4b, Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Profiling the Proteome-Wide Selectivity of Diverse Electrophiles

Zanon¹,

Yu²,

Zhang³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…25). 48 Exhibiting high lysine selectivity (81%) and good proteomic coverage (3796 quantified lysines, Fig. 4b, Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Profiling the proteome-wide selectivity of diverse electrophiles

Zanon

Zhang

et al. 2021

Preprint

View full text Add to dashboard Cite

Targeted covalent inhibitors are powerful entities in drug discovery, but their application has so far mainly been limited to addressing cysteine residues. The development of cysteine-directed covalent inhibitors has largely profited from determining their proteomewide selectivity using competitive residue-specific proteomics. Several probes have recently been described to monitor other amino acids using this technology and many more electrophiles exist to modify proteins. Nevertheless, a direct, proteome-wide comparison of the selectivity of diverse probes is still entirely missing. Here, we developed a completely unbiased workflow to analyse electrophile selectivity proteome-wide and applied it to directly compare 54 alkyne probes containing diverse reactive groups. In this way, we verified and newly identified probes to monitor a total of nine different amino acids as well as the N-terminus proteome-wide. This selection includes the first probes to globally monitor tryptophans, histidines and arginines as well as novel tailored probes for methionines, aspartates and glutamates.

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“…Conveniently, protein modification by reductive amination allows the positive charge on the N-terminus to be preserved, which could be crucial to retain, in some cases, protein bioactivity. Similarly, 2-ethynylbenzaldehyde (2-EBA) derivatives were reported to selectively react with the protein N-terminal alpha-amine group in phosphate-buffered saline solution at pH 6.5-7.4 through the formation of an isoquinolinium conjugate in which the nitrogen atom is positively charged (Figure 1b) [30]. A phthalimidation protocol using N-hydroxy-phthalimide reagents and targeting protein N-terminus has also been reported, showing selectivity against alpha-amine in the presence of lysine residues at pH 7.0 (Figure 1c) [31].…”

Section: Chemical Strategies Targeting Protein N-terminus 21 Direct Labeling Of Protein N-terminusmentioning

confidence: 99%

Exploiting Protein N-Terminus for Site-Specific Bioconjugation

et al. 2021

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Although a plethora of chemistries have been developed to selectively decorate protein molecules, novel strategies continue to be reported with the final aim of improving selectivity and mildness of the reaction conditions, preserve protein integrity, and fulfill all the increasing requirements of the modern applications of protein conjugates. The targeting of the protein N-terminal alpha-amine group appears a convenient solution to the issue, emerging as a useful and unique reactive site universally present in each protein molecule. Herein, we provide an updated overview of the methodologies developed until today to afford the selective modification of proteins through the targeting of the N-terminal alpha-amine. Chemical and enzymatic strategies enabling the selective labeling of the protein N-terminal alpha-amine group are described.

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N-Terminal selective modification of peptides and proteins using 2-ethynylbenzaldehydes

Cited by 34 publications

References 37 publications

Profiling the Proteome-Wide Selectivity of Diverse Electrophiles

Profiling the Proteome-Wide Selectivity of Diverse Electrophiles

Profiling the proteome-wide selectivity of diverse electrophiles

Exploiting Protein N-Terminus for Site-Specific Bioconjugation

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