Design and synthesis of Le(y)-bearing glycopeptides that mimic cell surface Le(y) mucin glycoprotein architecture

Five Lewis(y)-based glycopeptide anti-cancer vaccine candidates have been d esigned and synthesized to target tumor-associated cell-surface glycoprotei n antigens and to improve the immunizing performance in comparison to relat ed vaccines. The peptide backbone consisted of two regions, a glycodomain A cNH-SSS-and a nonglycosylated sequence,-AVAV-. The resultant glycopeptide w as conjugated, via an additional spacer, to the lipid carrier PamCysSer. In this series of totally synthetic molecular vaccine candidates, one or thre e of the sequentially arranged serine residues were glycosylated. Furthermo re, the Le(y) tetrasaccharide determinant region was kept constant while th e internal glycan core was systematically varied. Glycal assembly was used to prepare the glycosyl donors, and two strategies were applied to provide the serine-O-linked polysaccharide domains. In the first approach, a protec ted serine derivative was attached directly to the fully elaborated glycan. Following this course, both alpha- and beta-Ser derivatives were accessed. In the second route, a GalNAc-alpha-Ser was joined with a glycosyl donor t o afford exclusively the desired a-serine-linked product. The glycopeptides were assembled using iterative solution phase peptide coupling. Following global deprotection, the lipid carrier was then coupled to the glycopeptide , resulting in the targeted constructs. The synthesis of these molecular va ccine candidates constitutes an important advance that should enable ration alization of carbohydrate-induced immune response as well as identification of optimal Le(y)-based anti-cancer vaccine leads.