Direct Peptide Bioconjugation/PEGylation at Tyrosine with Linear and Branched Polymeric Diazonium Salts
2012
Jones, Mathew W. | Mantovani, Giuseppe | Blindauer, Claudia A. | Ryan, Sinead M. | Wang, Xuexuan | Brayden, David J. | Haddleton, David M.
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 mPEG₂₀₀₀ 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 [Ca²⁺] plasma levels by mPEG₂₀₀₀-sCT conjugate in rat animal models.
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