Site-Specific Poly(ethylene glycol)ylation of Peptides

摘要

In contrast ot proteins, peptides are ideal targets for PEGylation since they may be PEGylated usign modern orthogonal protection strategies. Synthetic conditions have been developed for the site-specific solid phase PEGylation (Fmoc/tBu strategy) at the NH_2-terminal, internal (at the side-chain of Lys/Orn or Glu/Asp) and at the COOH-terminal positions. Conditions for site-specific solution phase PEGylation have also been developed in which a Cys residue is introduced at any position into the peptied in which a Cys residue is introduced at any position into the peptide and subsequently PEGylated usign na activated dithiopyridyl-PEGylated peptides were prepared in which the PEG moieties were varied in molecular weight (i.e. degree of PEGylation; 750, 2000, 5000 and 10,000). Site-specific PEGylation of peptides enables the evaluation of the structure-activity relationships of biologically important peptides (i.e. the effect of site of PEGylation and degree of PEGylation on biological activity). These studies provide an importnat groundwork for the esign of PEGylatecd peptides which retain the groundwork for the design of PEGylated peptides which retain the desirable properties imposed by the incorporation of PEG (enhanced solubility, increased resistnace to proteolytic degradation, decreased antigenicity and immunogenicity) and have improved in vivo profiles.