The Use of Fluoroproline in MUC1 Antigen Enables Efficient Detection of Antibodies in Patients with Prostate Cancer

• Published in: Journal of the American Chemical Society 2017-12, Vol.139 (50), p.18255-18261
• Main Authors: Somovilla, Víctor J, Bermejo, Iris A, Albuquerque, Inês S, Martínez-Sáez, Nuria, Castro-López, Jorge, García-Martín, Fayna, Compañón, Ismael, Hinou, Hiroshi, Nishimura, Shin-Ichiro, Jiménez-Barbero, Jesús, Asensio, Juan L, Avenoza, Alberto, Busto, Jesús H, Hurtado-Guerrero, Ramón, Peregrina, Jesús M, Bernardes, Gonçalo J. L, Corzana, Francisco
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Antibodies - blood; Antibodies - chemistry; Binding Sites, Antibody; Crystallography, X-Ray; Drug Design; Humans; Molecular Dynamics Simulation; Mucin-1 - chemistry; Mucin-1 - genetics; Peptides - chemistry; Peptides - genetics; Proline - analogs & derivatives; Proline - chemistry
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.7b09447

A structure-based design of a new generation of tumor-associated glycopeptides with improved affinity against two anti-MUC1 antibodies is described. These unique antigens feature a fluorinated proline residue, such as a (4S)-4-fluoro-l-proline or 4,4-difluoro-l-proline, at the most immunogenic domain. Binding assays using biolayer interferometry reveal 3-fold to 10-fold affinity improvement with respect to the natural (glyco)­peptides. According to X-ray crystallography and MD simulations, the fluorinated residues stabilize the antigen–antibody complex by enhancing key CH/π interactions. Interestingly, a notable improvement in detection of cancer-associated anti-MUC1 antibodies from serum of patients with prostate cancer is achieved with the non-natural antigens, which proves that these derivatives can be considered better diagnostic tools than the natural antigen for prostate cancer.