title: Selective alkylation and acylation of alpha and epsilon amino groups with PEG in a somatostatin analogue: tailored chemistry for optimized bioconjugates.
abstract: The effects of the type and location of polymer grafting on the biological activity of different mono-PEG derivatives of the somatostatin analogue RC160 were evaluated. A chemical strategy to obtain mono-PEG alkylation or acylation of the peptide's alpha-terminal or lysil-epsilon primary amines was devised. Selective BOC protection of the two available primary amines, followed by reaction with two different PEG reagents and removal of the protecting group, was carried out. Chemical characterization, structural studies, and the evaluation of the biological activity of the bioconjugates synthesized allowed the identification of the one having characteristics more suitable for therapeutic application. This corresponds to the mono-epsilon-lysil-pegylated form, obtained by reductive alkylation, where the amine's positive charge is preserved. The results obtained suggest the importance of preliminary studies in the development of new polymer-peptide conjugates with improved pharmacological properties.
authors.affiliation: Universitá degli Studi di Padova, Dipartimento Scienze Farmaceutiche, via Marzolo, 5, 35131 Padova, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Morpurgo
authors.forename: Cristina
authors.initials: C
authors.lastname: Monfardini
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Hofland
authors.forename: Mauro
authors.initials: M
authors.lastname: Sergi
authors.forename: Paolo
authors.initials: P
authors.lastname: Orsolini
authors.forename: Jean M
authors.initials: JM
authors.lastname: Dumont
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Veronese
mesh_terms: D000215:Acylation; D000478:Alkylation; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D013006:Growth Hormone / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008297:Male; D015394:Molecular Structure; D010903:Pituitary Gland, Anterior / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: C051458:vapreotide; D011092:Polyethylene Glycols; D013004:Somatostatin; D013006:Growth Hormone