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Mucin architecture behind the immune response: design, evaluation and conformational analysis of an antitumor vaccine derived from an unnatural MUC1 fragment.
Martínez-Sáez, Nuria; Supekar, Nitin T; Wolfert, Margreet A; Bermejo, Iris A; Hurtado-Guerrero, Ramón; Asensio, Juan L; Jiménez-Barbero, Jesús; Busto, Jesús H; Avenoza, Alberto; Boons, Geert-Jan; Peregrina, Jesús M; Corzana, Francisco.
Afiliação
  • Martínez-Sáez N; Departamento de Química , Universidad de La Rioja , Centro de Investigación en Síntesis Química , Madre de Dios 53 , 26006 Logroño , Spain . Email: francisco.corzana@unirioja.es ; Email: jesusmanuel.peregrina@unirioja.es.
  • Supekar NT; Complex Carbohydrate Research Center , University of Georgia , 315 Riverbend Road , Athens , Georgia 30602 , USA . Email: gjboons@ccrc.uga.edu.
  • Wolfert MA; Complex Carbohydrate Research Center , University of Georgia , 315 Riverbend Road , Athens , Georgia 30602 , USA . Email: gjboons@ccrc.uga.edu.
  • Bermejo IA; Departamento de Química , Universidad de La Rioja , Centro de Investigación en Síntesis Química , Madre de Dios 53 , 26006 Logroño , Spain . Email: francisco.corzana@unirioja.es ; Email: jesusmanuel.peregrina@unirioja.es.
  • Hurtado-Guerrero R; BIFI , University of Zaragoza , BIFI-IQFR (CSIC) Joint Unit , Mariano Esquillor s/n , Campus Rio Ebro , Edificio I+D , Zaragoza , Spain.
  • Asensio JL; Fundación ARAID , 50018 , Zaragoza , Spain.
  • Jiménez-Barbero J; Instituto de Química Orgánica General , IQOG-CSIC , Juan de la Cierva 3 , 28006 Madrid , Spain.
  • Busto JH; Structural Biology Unit , CIC bioGUNE , Parque Tecnológico de Bizkaia Building 801A , 48160 Derio , Spain.
  • Avenoza A; IKERBASQUE , Basque Foundation for Science , 48011 Bilbao , Spain.
  • Boons GJ; Department of Chemical and Physical Biology , Centro de Investigaciones Biológicas , CSIC , Ramiro de Maeztu 9 , 28040 Madrid , Spain.
  • Peregrina JM; Departamento de Química , Universidad de La Rioja , Centro de Investigación en Síntesis Química , Madre de Dios 53 , 26006 Logroño , Spain . Email: francisco.corzana@unirioja.es ; Email: jesusmanuel.peregrina@unirioja.es.
  • Corzana F; Departamento de Química , Universidad de La Rioja , Centro de Investigación en Síntesis Química , Madre de Dios 53 , 26006 Logroño , Spain . Email: francisco.corzana@unirioja.es ; Email: jesusmanuel.peregrina@unirioja.es.
Chem Sci ; 7(3): 2294-2301, 2016 Mar 01.
Article em En | MEDLINE | ID: mdl-29910919
ABSTRACT
A tripartite cancer vaccine candidate, containing a quaternary amino acid (α-methylserine) in the most immunogenic domain of MUC1, has been synthesized and examined for antigenic properties in transgenic mice. The vaccine which is glycosylated with GalNAc at the unnatural amino acid, was capable of eliciting potent antibody responses recognizing both glycosylated and unglycosylated tumour-associated MUC1 peptides and native MUC1 antigen present on cancer cells. The peptide backbone of the novel vaccine presents the bioactive conformation in solution and is more resistant to enzymatic degradation than the natural counter part. In spite of these features, the immune response elicited by the unnatural vaccine was not improved compared to a vaccine candidate containing natural threonine. These observations were rationalized by conformational studies, indicating that the presentation and dynamics of the sugar moiety displayed by the MUC1 derivative play a critical role in immune recognition. It is clear that engineered MUC1-based vaccines bearing unnatural amino acids have to be able to emulate the conformational properties of the glycosidic linkage between the GalNAc and the threonine residues. The results described here will be helpful to the rational design of efficacious cancer vaccines.

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2016 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2016 Tipo de documento: Article