Design of α-S-Neoglycopeptides Derived from MUC1 with a Flexible and Solvent-Exposed Sugar Moiety

Víctor Rojas-Ocáriz; Ismael Compañón; Carlos Aydillo Miguel; Jorge Castro-Loṕez; Jesús Jiménez-Barbero; Ramón Hurtado-Guerrero; Alberto Avenoza; María M. Zurbano; Jesús M. Peregrina; Jesús H. Busto; Francisco Corzana

doi:10.1021/acs.joc.6b00833

Design of α-S-Neoglycopeptides Derived from MUC1 with a Flexible and Solvent-Exposed Sugar Moiety

Víctor Rojas-Ocáriz, Ismael Compañón, Carlos Aydillo Miguel, Jorge Castro-Loṕez, Jesús Jiménez-Barbero, Ramón Hurtado-Guerrero, Alberto Avenoza, María M. Zurbano, Jesús M. Peregrina^*, Jesús H. Busto, Francisco Corzana

^*Corresponding author for this work

Department of Chemistry

14 Citations (Scopus)

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.

Original language	English
Journal	The Journal of Organic Chemistry
Volume	81
Issue number	14
Pages (from-to)	5929-5941
Number of pages	13
ISSN	0022-3263
DOIs	https://doi.org/10.1021/acs.joc.6b00833
Publication status	Published - 2016

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Rojas-Ocáriz, V., Compañón, I., Aydillo Miguel, C., Castro-Loṕez, J., Jiménez-Barbero, J., Hurtado-Guerrero, R., Avenoza, A., Zurbano, M. M., Peregrina, J. M., Busto, J. H., & Corzana, F. (2016). Design of α-S-Neoglycopeptides Derived from MUC1 with a Flexible and Solvent-Exposed Sugar Moiety. The Journal of Organic Chemistry, 81(14), 5929-5941. https://doi.org/10.1021/acs.joc.6b00833

Rojas-Ocáriz, V, Compañón, I, Aydillo Miguel, C, Castro-Loṕez, J, Jiménez-Barbero, J, Hurtado-Guerrero, R, Avenoza, A, Zurbano, MM, Peregrina, JM, Busto, JH & Corzana, F 2016, 'Design of α-S-Neoglycopeptides Derived from MUC1 with a Flexible and Solvent-Exposed Sugar Moiety', The Journal of Organic Chemistry, vol. 81, no. 14, pp. 5929-5941. https://doi.org/10.1021/acs.joc.6b00833

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title = "Design of α-S-Neoglycopeptides Derived from MUC1 with a Flexible and Solvent-Exposed Sugar Moiety",

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.",

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AU - Rojas-Ocáriz, Víctor

AU - Compañón, Ismael

AU - Aydillo Miguel, Carlos

AU - Castro-Loṕez, Jorge

AU - Jiménez-Barbero, Jesús

AU - Hurtado-Guerrero, Ramón

AU - Avenoza, Alberto

AU - Zurbano, María M.

AU - Peregrina, Jesús M.

AU - Busto, Jesús H.

AU - Corzana, Francisco

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AB - 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.

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JF - Journal of Organic Chemistry

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ER -

Design of α-S-Neoglycopeptides Derived from MUC1 with a Flexible and Solvent-Exposed Sugar Moiety

Abstract

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