Mucin-type O-glycosylation and its potential use in drug and vaccine development.
Mucin-type O-glycans are found on mucins as well as many other glycoproteins. The initiation step in synthesis is catalyzed by a large family of polypeptide GalNAc-transferases attaching the first carbohydrate residue, GalNAc, to selected serine and threonine residues in proteins. During the last decade an increasing number of GalNAc-transferase isoforms have been cloned and their substrate-specificities partly characterized. These differences in substrate specificities have been exploited for in vitro site-directed O-glycosylation. In GlycoPEGylation, polyehylene glycol (PEG) is transferred to recombinant therapeutics to specific acceptor sites directed by GalNAc-transferases. GalNAc-transferases have also been used to control density of glycosylation in the development of glycopeptide-based cancer vaccines. The membrane-associated mucin-1 (MUC1) has long been considered a target for immunotherapeutic and immunodiagnostic measures, since it is highly overexpressed and aberrantly O-glycosylated in most adenocarcinomas, including breast, ovarian, and pancreatic cancers. By using vaccines mimicking the glycosylation pattern of cancer-cells, it is possible to overcome tolerance in transgenic animals expressing the human MUC1 protein as a self-antigen providing important clues for an improved MUC1 vaccine design. The present review will highlight some of the potential applications of site-directed O-glycosylation.
Tarp
Mads Agervig
MA
Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, The Panum Institute, 6.4, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. mpt@imbg.ku.dk
Clausen
Henrik
H
D000818:Animals; D019496:Cancer Vaccines / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D006031:Glycosylation; D006801:Humans; D009077:Mucins / Q000378:metabolism*; D017350:N-Acetylgalactosaminyltransferases / Q000378:metabolism; D000097763:Polypeptide N-acetylgalactosaminyltransferase
D019496:Cancer Vaccines; D009077:Mucins; D017350:N-Acetylgalactosaminyltransferases; D000097763:Polypeptide N-acetylgalactosaminyltransferase