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

  1. Rojas-Ocáriz, V. 3
  2. Compañón, I. 3
  3. Aydillo, C. 23
  4. Castro-Loṕez, J. 1
  5. Jiménez-Barbero, J. 46
  6. Hurtado-Guerrero, R. 15
  7. Avenoza, A. 3
  8. Zurbano, M.M. 3
  9. Peregrina, J.M. 3
  10. Busto, J.H. 3
  11. Corzana, F. 3
  1. 1 Universidad de Zaragoza
    info

    Universidad de Zaragoza

    Zaragoza, España

    ROR https://ror.org/012a91z28

  2. 2 University of Copenhagen
    info

    University of Copenhagen

    Copenhague, Dinamarca

    ROR https://ror.org/035b05819

  3. 3 Universidad de La Rioja
    info

    Universidad de La Rioja

    Logroño, España

    ROR https://ror.org/0553yr311

  4. 4 Centro de Investigaciones Biológicas
    info

    Centro de Investigaciones Biológicas

    Madrid, España

    ROR https://ror.org/04advdf21

  5. 5 Fundación Agencia Aragonesa para la Investigación y el Desarrollo
    info

    Fundación Agencia Aragonesa para la Investigación y el Desarrollo

    Zaragoza, España

  6. 6 Ikerbasque, Fundación Vasca para la Ciencia
    info

    Ikerbasque, Fundación Vasca para la Ciencia

    Bilbao, España

    ROR https://ror.org/01cc3fy72

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Revista:
Journal of Organic Chemistry

ISSN: 0022-3263

Año de publicación: 2016

Volumen: 81

Número: 14

Páginas: 5929-5941

Tipo: Artículo

DOI: 10.1021/ACS.JOC.6B00833 SCOPUS: 2-s2.0-84978517876 WoS: WOS:000380181500013 GOOGLE SCHOLAR

Otras publicaciones en: Journal of Organic Chemistry

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Resumen

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.