Design of α-S-Neoglycopeptides Derived from MUC1 with a Flexible and Solvent-Exposed Sugar Moiety
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- 作者：Víctor Rojas-Ocáriz ; Ismael Compañón ; Carlos Aydillo ; Jorge Castro-Loṕez ; Jesús Jiménez-Barbero ; Ramón Hurtado-Guerrero ; Alberto Avenoza ; María M. Zurbano ; Jesús M. Peregrina ; Jesús H. Busto ; Francisco Corzana
- 刊名：Journal of Organic Chemistry
- 出版年：2016
- 出版时间：July 15, 2016
- 年：2016
- 卷：81
- 期：14
- 页码：5929-5941
- 全文大小：741K
- 年卷期：0
- ISSN：1520-6904
文摘
The use of vaccines based on MUC1 glycopeptides is a promising approach to treat cancer. We present herein several sulfa-Tn antigens incorporated in MUC1 sequences that possess a variable linker between the carbohydrate (GalNAc) and the peptide backbone. The main conformations of these molecules in solution have been evaluated by combining NMR experiments and molecular dynamics simulations. The linker plays a key role in the modulation of the conformation of these compounds at different levels, blocking a direct contact between the sugar moiety and the backbone, promoting a helix-like conformation for the glycosylated residue and favoring the proper presentation of the sugar unit for molecular recognition events. The feasibility of these novel compounds as mimics of MUC1 antigens has been validated by the X-ray diffraction structure of one of these unnatural derivatives complexed to an anti-MUC1 monoclonal antibody. These features, together with potential lack of immune suppression, render these unnatural glycopeptides promising candidates for designing alternative therapeutic vaccines against cancer.