In Situ Maleimide Bridging of Disulfides and a New Approach to Protein PEGylation

被引：118

作者：

Schumacher, Felix F. ^{[1
]}

Nobles, Muriel ^{[2
]}

Ryan, Chris P. ^{[1
]}

Smith, Mark E. B. ^{[1
]}

Tinker, Andrew ^{[2
]}

Caddick, Stephen ^{[1
]}

Baker, James R. ^{[1
]}

机构：

[1] UCL, Dept Chem, London WC1H OAJ, England

[2] UCL, Dept Med, London WC1E 6JJ, England

来源：

BIOCONJUGATE CHEMISTRY | 2011年 / 22卷 / 02期

基金：

英国生物技术与生命科学研究理事会; 英国惠康基金;

关键词：

SOMATOSTATIN ANALOGS; BONDS; REDUCTION;

D O I：

10.1021/bc1004685

中图分类号：

Q5 [生物化学];

学科分类号：

071010 ; 081704 ;

摘要：

The introduction of non-natural entities into proteins by chemical modification has numerous applications in fundamental biological science and for the development and manipulation of peptide and protein therapeutics. The reduction of native disulfide bonds provides a convenient method to access two nucleophilic cysteine residues that can serve as ideal attachment points for such chemical modification. The optimum bioconjugation strategy utilizing these cysteine residues should include the reconstruction of a bridge to mimic the role of the disulfide bond, maintaining structure and stability of the protein. Furthermore, the bridging chemical modification should be as rapid as possible to prevent problems associated with protein unfolding, aggregation, or disulfide scrambling. This study reports on an in situ disulfide reduction-bridging strategy that ensures rapid sequestration of the free cysteine residues in a bridge, using dithiomaleimides. This approach is then used to PEGylate the peptide hormone somatostatin and retention of biological activity is demonstrated.

引用

页码：132 / 136

页数：5

共 27 条

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[3]

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[4]

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