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Towards a Fully Synthetic MUC1‐Based Anticancer Vaccine: Efficient Conjugation of Glycopeptides with Mono‐, Di‐, and Tetravalent Lipopeptides Using Click Chemistry

2011; Wiley; Volume: 17; Issue: 23 Linguagem: Inglês

10.1002/chem.201100217

1521-3765

Hui Cai, Zhi‐Hua Huang, Lei Shi, Yufen Zhao, Horst Kunz, Yanmei Li,

Click Chemistry and Applications

Abstract The membrane‐bound tumor‐associated glycoprotein MUC1 is aberrantly glycosylated in cancer cells compared with normal cells, and is therefore considered an attractive target for cancer immunotherapy. However, tumor‐associated glycopeptides from MUC1 do not elicit a sufficiently robust immune response. Therefore, antitumor vaccines were developed, which consist of MUC1 glycopeptides as the B epitopes and immune‐stimulating toll‐like receptor 2 (TLR 2) lipopeptide ligands. These fully synthetic vaccine candidates were prepared by solid‐phase synthesis of the MUC1 glycopeptides. The Pam 3 Cys lipopeptide, also synthesized on solid‐phase, was C‐terminally coupled to oligovalent lysine cores, which N‐terminally incorporate O ‐propargyl oligoethylene glycol acyl side chains. The MUC1 glycopeptides and lipopeptide lysine constructs were then conjugated by click chemistry to give oligovalent synthetic vaccines. Oligovalent glycopeptide–lipopeptide conjugates are considered more immunogenic than their monovalent analogues.