title: Direct peptide bioconjugation/PEGylation at tyrosine with linear and branched polymeric diazonium salts.
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.
authors.affiliation: Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: Mathew W
authors.initials: MW
authors.lastname: Jones
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mantovani
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Blindauer
authors.forename: Sinead M
authors.initials: SM
authors.lastname: Ryan
authors.forename: Xuexuan
authors.initials: X
authors.lastname: Wang
authors.forename: David J
authors.initials: DJ
authors.lastname: Brayden
authors.forename: David M
authors.initials: DM
authors.lastname: Haddleton
mesh_terms: D000818:Animals; D002116:Calcitonin / Q000737:chemistry* / Q000494:pharmacology; D002118:Calcium / Q000097:blood; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D003979:Diazonium Compounds / Q000737:chemistry*; D004743:Enkephalin, Leucine / Q000737:chemistry*; D006801:Humans; D008297:Male; D008689:Methacrylates / Q000737:chemistry*; D008958:Models, Molecular; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D014443:Tyrosine / Q000737:chemistry*
chemical_list: D003979:Diazonium Compounds; D008689:Methacrylates; D011092:Polyethylene Glycols; D014443:Tyrosine; D004743:Enkephalin, Leucine; C028815:salmon calcitonin; C028210:monomethoxypolyethylene glycol; D002116:Calcitonin; D000242:Cyclic AMP; D002118:Calcium