Direct peptide bioconjugation/PEGylation at tyrosine with linear and branched polymeric diazonium salts

Mathew W. Jones, Giuseppe Mantovani, Claudia A. Blindauer, Sinead M. Ryan, Xuexuan Wang, David J. Brayden, David M. Haddleton

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Abstract

Direct polymer conjugation at peptide tyrosine residues is described. In this study Tyr residues of both leucine enkephalin and salmon calcitonin (sCT) were targeted using appropriate diazonium salt-terminated linear monomethoxy poly(ethylene glycol)s (mPEGs) and poly(mPEG) methacrylate prepared by atom transfer radical polymerization. Judicious choice of the reaction conditions-pH, stoichiometry, and chemical structure of diazonium salt-led to a high degree of site-specificity in the conjugation reaction, even in the presence of competitive peptide amino acid targets such as histidine, lysines, and N-terminal amine. In vitro studies showed that conjugation of mPEG 2000 to sCT did not affect the peptide's ability to increase intracellular cAMP induced in T47D human breast cancer cells bearing sCT receptors. Preliminary in vivo investigation showed preserved ability to reduce [Ca 2+] plasma levels by mPEG 2000-sCT conjugate in rat animal models.

Original languageEnglish
Pages (from-to)7406-7413
Number of pages8
JournalJournal of the American Chemical Society
Volume134
Issue number17
DOIs
Publication statusPublished - 2 May 2012
Externally publishedYes

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