Synthetic vaccines based on N- and O-glycopeptides–molecular tools for immunotherapy and diagnostics

Abstract

This chapter summarizes available methods for the preparation of synthetic vaccines based on glycopeptides and recent advances in this field. It further includes results of their immunological evaluation. Syntheses of glycopeptides of defined chemical structure and conjugation of these compounds to a carrier protein or an immunostimulant are of interest for the development of new immunotherapeutics and/or antibody-based diagnostics. Since a number of years, the aberrant glycosylation of the tumorassociated mucin MUC1 forming tumor specific epitopes on the epithelial cell surface has been considered an attractive research target for the preparation of such vaccines. Examples of synthetic vaccines directed against the O-glycosylated MUC1 tandem repeats will here be given including synthetic MUC1 glycopeptides conjugated to a T-cell epitope peptide, to a carrier protein, to a lipid immunostimulant or the multimeric presentation of glycopeptides on dendrimers. Other attractive targets for immunotherapy are the viral envelope proteins HIV gp120 and HIV gp41 , which are highly glycosylated with high-mannose and complex type Nglycans. Examples will be given, which illustrate syntheses of high-mannose HIV gp120 or gp41 glycopeptides with the natural peptide backbone or with a nonnatural cyclic backbone to mimic the high-mannose cluster domain of HIV gp120. In addition the synthesis and immunological evaluation of a vaccine will be described, which contains the high-mannose cluster mimotope glycopeptide conjugated to an outer membrane protein complex (OMPC) as the carrier.

Sialyl-Tn in Cancer: (How) Did We Miss the Target?

“…Glycopeptide dendrimers have therefore been developed to simultaneously present different carbohydrate antigens such as STn, Tn, T, Globo H, G M2 , Lewis y , and MUC1-Tn antigens. Presently, the challenge of efficiently preparing carbohydrate clusters was solved at the level of chemical synthesis [ 166 ]. These constructs and their application in pre-clinical and clinical trials have been reviewed elsewhere [ 167 , 168 ].…”

Divergent Behavior of Glycosylated Threonine and Serine Derivatives in Solid Phase Peptide Synthesis

“…Glycopeptides are also being developed as vaccines for cancer and HIV, and several have progressed into clinical trials. 2,7–9 …”