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. 2021 Feb 18;12(14):5209-5215.
doi: 10.1039/d0sc06576e.

Cleavable and tunable cysteine-specific arylation modification with aryl thioethers

Jian Li  1 , Jun-Jie Deng  1 , Zhibin Yin  1 , Qi-Long Hu  1 , Yang Ge  1 , Zhendong Song  1 , Ying Zhang  1 , Albert S C Chan  1 , Huilin Li  1 , Xiao-Feng Xiong  1
Affiliations

Cleavable and tunable cysteine-specific arylation modification with aryl thioethers

Jian Li et al. Chem Sci. .

Abstract

Cysteine represents an attractive target for peptide/protein modification due to the intrinsic high nucleophilicity of the thiol group and low natural abundance. Herein, a cleavable and tunable covalent modification approach for cysteine containing peptides/proteins with our newly designed aryl thioethers via a S N Ar approach was developed. Highly efficient and selective bioconjugation reactions can be carried out under mild and biocompatible conditions. A series of aryl groups bearing different bioconjugation handles, affinity or fluorescent tags are well tolerated. By adjusting the skeleton and steric hindrance of aryl thioethers slightly, the modified products showed a tunable profile for the regeneration of the native peptides.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. (A) Representative reagents for Cys modification based on nucleophilic aromatic substitution. (B) Representative cleavable cysteine specific modification reagents. (C) Cleavable and tunable cysteine arylation strategy via a SNAr mechanism.
Fig. 2
Fig. 2. Substrate scope of cysteine arylation. Unless otherwise specified, all reactions were carried out with 1.0 μmol 1a and 3 μmol 2 in 1 mL 100 mM Tris buffer (pH 8.0, 1% v/v DMSO) at room temperature for 1 h. Reported yields are LC-MS yields. aThe reaction was analysed after 5 min. bThe reaction was analysed after 5 h. c5% DMSO was added.
Fig. 3
Fig. 3. Substrate scope of cysteine-containing peptides. Unless otherwise specified, all reactions were carried out with 1.0 μmol 1a and 3 μmol 2 in 1 mL 100 mM Tris buffer (pH 8.0, 1% v/v DMSO) at room temperature for 1 h. Reported yields are LC-MS yields after 1 h. aThe reaction was analysed after 5 min. b5% DMSO was added.
Fig. 4
Fig. 4. (A) Regeneration activity evaluation of modified peptides. Reported yields are LC-MS yields of 1a regenerated from 3 with βME after 1 h. (The yields in parentheses correspond to the yields of 1a regenerated from 3 with GSH after 1 h). (B) Substrate scope of peptide regeneration. Reported yields are LC-MS yields of peptides 1 regenerated from 2j and 2ad modified peptides 3 with βME after 1 h.
Fig. 5
Fig. 5. (A) BSA modification with 2v. (B) ESI-MS spectra of native BSA and modified BSA-2v proteins. (C) Secondary labeling of modified peptide 3ss.
See this image and copyright information in PMC

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