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Electrochemical oxidation induced selective tyrosine bioconjugation for the modification of biomolecules.

ABSTRACT: Directly introducing a beneficial functional group into biomolecules under mild, clean and easy-to-handle conditions is of great importance in the field of chemical biology and pharmacology. Herein, we described an electrochemical strategy to perform the bioconjugation of tyrosine residues with phenothiazine derivatives in a rapid and simple manner. In this electrochemical system, various polypeptides and proteins were successfully labelled with excellent site- and chemo-selectivity, and metals, oxidants or additives were also avoided.

SUBMITTER: Song C

PROVIDER: S-EPMC6788519 | biostudies-other | 2019 Sep

REPOSITORIES: biostudies-other

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Electrochemical oxidation induced selective tyrosine bioconjugation for the modification of biomolecules.

Song Chunlan C Liu Kun K Wang Zhongjie Z Ding Bo B Wang Shengchun S Weng Yue Y Chiang Chien-Wei CW Lei Aiwen A

Chemical science 20190708 34

Directly introducing a beneficial functional group into biomolecules under mild, clean and easy-to-handle conditions is of great importance in the field of chemical biology and pharmacology. Herein, we described an electrochemical strategy to perform the bioconjugation of tyrosine residues with phenothiazine derivatives in a rapid and simple manner. In this electrochemical system, various polypeptides and proteins were successfully labelled with excellent site- and chemo-selectivity, and metals, ...[more]

PMID: 31673320

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Project description:The scope, chemoselectivity, and utility of the click-like tyrosine labeling reaction with 4-phenyl-3H-1,2,4-triazoline-3,5(4H)-diones (PTADs) is reported. To study the utility and chemoselectivity of PTAD derivatives in peptide and protein chemistry, we synthesized PTAD derivatives possessing azide, alkyne, and ketone groups and studied their reactions with amino acid derivatives and peptides of increasing complexity. With proteins we studied the compatibility of the tyrosine click reaction with cysteine and lysine-targeted labeling approaches and demonstrate that chemoselective trifunctionalization of proteins is readily achieved. In particular cases, we noted that PTAD decomposition resulted in formation of a putative isocyanate byproduct that was promiscuous in labeling. This side reaction product, however, was readily scavenged by the addition of a small amount of 2-amino-2-hydroxymethyl-propane-1,3-diol (Tris) to the reaction medium. To study the potential of the tyrosine click reaction to introduce poly(ethylene glycol) chains onto proteins (PEGylation), we demonstrate that this novel reagent provides for the selective PEGylation of chymotrypsinogen, whereas traditional succinimide-based PEGylation targeting lysine residues provided a more diverse range of PEGylated products. Finally, we applied the tyrosine click reaction to create a novel antibody-drug conjugate. For this purpose, we synthesized a PTAD derivative linked to the HIV entry inhibitor aplaviroc. Labeling of the antibody trastuzumab with this reagent provided a labeled antibody conjugate that demonstrated potent HIV-1 neutralization activity demonstrating the potential of this reaction in creating protein conjugates with small molecules. The tyrosine click linkage demonstrated stability to extremes of pH, temperature, and exposure to human blood plasma indicating that this linkage is significantly more robust than maleimide-type linkages that are commonly employed in bioconjugations. These studies support the broad utility of this reaction in the chemoselective modification of small molecules, peptides, and proteins under mild aqueous conditions over a broad pH range using a wide variety of biologically acceptable buffers such as phosphate buffered saline (PBS) and 2-amino-2-hydroxymethyl-propane-1,3-diol (Tris) buffers as well as others and mixed buffered compositions.

Dataset Information

Electrochemical oxidation induced selective tyrosine bioconjugation for the modification of biomolecules.

Publications

Electrochemical oxidation induced selective tyrosine bioconjugation for the modification of biomolecules.

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