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

Selective modification of the N-terminus of peptides and proteins is a promising strategy for single site modification methods. Here we report N-terminal selective modification of peptides and proteins by using 2-ethynylbenzaldehydes (2-EBA) for the production of well-defined bioconjugates. After re...

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Bibliographic Details
Published in:Communications chemistry 2020-05, Vol.3 (1), p.67-67, Article 67
Main Authors: 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-Kin
Format: Article
Language:English
Subjects:
101/58
631/92/2783
639/638/549/933
82
Alkynes
Amino acids
Chemistry
Chemistry and Materials Science
Chemistry/Food Science
Cycloaddition
Fluorescein
Functional groups
Lysozyme
Peptides
Proteins
Rhodamine
Ribonuclease A
Selectivity
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Summary:Selective modification of the N-terminus of peptides and proteins is a promising strategy for single site modification methods. Here we report N-terminal selective modification of peptides and proteins by using 2-ethynylbenzaldehydes (2-EBA) for the production of well-defined bioconjugates. After reaction screening with a series of 2-EBA, excellent N-terminal selectivity is achieved by the reaction in slightly acidic phosphate-buffered saline using 2-EBA with electron-donating substituents. Selective modification of a library of peptides XSKFR (X = either one of 20 natural amino acids) by 2-ethynyl-4-hydroxy-5-methoxybenzaldehyde ( 2d ) results in good-to-excellent N-terminal selectivity in peptides (up to >99:1). Lysozyme, ribonuclease A and a therapeutic recombinant Bacillus caldovelox arginase mutant (BCArg mutant) are N-terminally modified using alkyne- and fluorescein-linked 2-EBA. Alkyne-linked BCArg mutant is further modified by rhodamine azide via copper(I)-catalyzed [3 + 2] cycloaddition indicating that the reaction has high functional group compatibility. Moreover, the BCArg mutant modified by 2-ethynyl-5-methoxybenzaldehyde ( 2b ) exhibits comparable activity in enzymatic and cytotoxic assays with the unmodified one. Selective functionalisation of the N-terminus of peptides and proteins may offer a useful tool for single-site modification. Here a general method for selective N-terminal labeling of peptides is reported, based on cyclisation of ethynylbenzaldehyde to form stable isoquinolinium salts.
ISSN:2399-3669
2399-3669
DOI:10.1038/s42004-020-0309-y