Design and Synthesis of Ley-Bearing Glycopeptides that Mimic Cell Surface Ley Mucin Glycoprotein Architecture
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- 作者：Peter W. Glunz ; Samuel Hintermann ; Lawrence J. Williams ; Jacob B. Schwarz ; Scott D. Kuduk ; Valery Kudryashov ; Kenneth O. Lloyd ; and Samuel J. Danishefsky
- 刊名：Journal of the American Chemical Society
- 出版年：2000
- 出版时间：August 2, 2000
- 年：2000
- 卷：122
- 期：30
- 页码：7273 - 7279
- 全文大小：382K
- 年卷期：v.122,no.30(August 2, 2000)
- ISSN：1520-5126
文摘
Five Lewisy-based glycopeptide anti-cancer vaccine candidates have been designed and synthesizedto target tumor-associated cell-surface glycoprotein antigens and to improve the immunizing performance incomparison to related vaccines. The peptide backbone consisted of two regions, a glycodomain AcNH-SSS-and a nonglycosylated sequence, -AVAV-. The resultant glycopeptide was conjugated, via an additional spacer,to the lipid carrier PamCysSer. In this series of totally synthetic molecular vaccine candidates, one or three ofthe sequentially arranged serine residues were glycosylated. Furthermore, the Ley tetrasaccharide determinantregion was kept constant while the internal glycan core was systematically varied. Glycal assembly was usedto prepare the glycosyl donors, and two strategies were applied to provide the serine-O-linked polysaccharidedomains. In the first approach, a protected serine derivative was attached directly to the fully elaborated glycan.Following this course, both 
- and 
-Ser derivatives were accessed. In the second route, a GalNAc--Ser wasjoined with a glycosyl donor to afford exclusively the desired -serine-linked product. The glycopeptideswere assembled using iterative solution phase peptide coupling. Following global deprotection, the lipid carrierwas then coupled to the glycopeptide, resulting in the targeted constructs. The synthesis of these molecularvaccine candidates constitutes an important advance that should enable rationalization of carbohydrate-inducedimmune response as well as identification of optimal Ley-based anti-cancer vaccine leads.
- and -Ser derivatives were accessed. In the second route, a GalNAc--Ser wasjoined with a glycosyl donor to afford exclusively the desired -serine-linked product. The glycopeptideswere assembled using iterative solution phase peptide coupling. Following global deprotection, the lipid carrierwas then coupled to the glycopeptide, resulting in the targeted constructs. The synthesis of these molecularvaccine candidates constitutes an important advance that should enable rationalization of carbohydrate-inducedimmune response as well as identification of optimal Ley-based anti-cancer vaccine leads.