A structure-based approach to designing non-natural peptides that can activate anti-melanoma cytotoxic T cells.
Tumor antigens presented by major histocompatibility complex (MHC) class I molecules and recognized by CD8(+) cytotoxic T lymphocytes (CTLs) may generate an efficient antitumor immune response after appropriate immunization. Antigenic peptides can be used in vivo to induce antitumor or antiviral immunity. The efficiency of naked peptides may be greatly limited by their degradation in the biological fluids. We present a rational, structure-based approach to design structurally modified, peptidase-resistant and biologically active analogues of human tumor antigen MAGE-1.A1. This approach is based on our understanding of the peptide interaction with the MHC and the T cell receptor and its precise degradation pathway. Knowledge of these mechanisms led to the design of a non-natural, minimally modified analogue of MAGE-1.A1, [Aib2, NMe-Ser8]MAGE-1.A1, which was highly peptidase-resistant and bound to MHC and activated MAGE-1.A1-specific anti-melanoma CTLs. Thus, we showed that it is possible to structurally modify peptide epitopes to obtain analogues that are still specifically recognized by CTLs. Such analogues may represent interesting leads for antitumor synthetic vaccines.
Ayyoub
M
M
Institut de Pharmacologie et Biologie Structurale, UPR 9062 CNRS, 205 route de Narbonne, 31400 Toulouse, France.
Mazarguil
H
H
Monsarrat
B
B
Van den Eynde
B
B
Gairin
J E
JE
D019943:Amino Acid Substitution; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D015195:Drug Design; D015788:HLA-A1 Antigen / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects*; D013058:Mass Spectrometry; D008545:Melanoma / Q000276:immunology*; D058950:Melanoma-Specific Antigens; D008958:Models, Molecular; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000138:chemical synthesis* / Q000235:genetics / Q000276:immunology*; D017354:Point Mutation; D013329:Structure-Activity Relationship; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000951:Antigens, Neoplasm; D015788:HLA-A1 Antigen; C072011:MAGEA1 protein, human; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins