Design of α-S-Neoglycopeptides Derived from MUC1 with a Flexible and Solvent-Exposed Sugar Moiety
- Rojas-Ocáriz, V. 3
- Compañón, I. 3
- Aydillo, C. 23
- Castro-Loṕez, J. 1
- Jiménez-Barbero, J. 46
- Hurtado-Guerrero, R. 15
- Avenoza, A. 3
- Zurbano, M.M. 3
- Peregrina, J.M. 3
- Busto, J.H. 3
- Corzana, F. 3
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1
Universidad de Zaragoza
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2
University of Copenhagen
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3
Universidad de La Rioja
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4
Centro de Investigaciones Biológicas
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5
Fundación Agencia Aragonesa para la Investigación y el Desarrollo
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Fundación Agencia Aragonesa para la Investigación y el Desarrollo
Zaragoza, España
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6
Ikerbasque, Fundación Vasca para la Ciencia
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ISSN: 0022-3263
Year of publication: 2016
Volume: 81
Issue: 14
Pages: 5929-5941
Type: Article
More publications in: Journal of Organic Chemistry
Abstract
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. © 2016 American Chemical Society.