Synthetic anticancer vaccine candidates: rational design of antigenic peptide mimetics that activate tumor-specific T-cells.
A rational design approach was followed to develop peptidomimetic analogues of a cytotoxic T-cell epitope capable of stimulating T-cell responses as strong as or stronger (heteroclytic) than those of parental antigenic peptides. The work described herein focused on structural alterations of the central amino acids of the melanoma tumor-associated antigenic peptide Melan-A/MART-1(26-35) using nonpeptidic units. A screening was first realized in silico to select altered peptides potentially capable of fitting at the interface between the major histocompatibilty complex (MHC) class-I HLA-A2 molecule and T-cell receptors (TCRs). Two compounds appeared to be high-affinity ligands to the HLA-A2 molecule and stimulated several Melan-A/MART-1 specific T-cell clones. Most remarkably, one of them even managed to amplify the response of one clone. Together, these results indicate that central TCR-contact residues of antigenic peptides can be replaced by nonpeptidic motifs without loss of binding affinity to MHC class-I molecules and T-cell triggering capacity.
Douat-Casassus
Céline
C
Institut Européen de Chimie et Biologie, 2 rue Robert Escarpit, 33607 Pessac Cedex, France.
Marchand-Geneste
Nathalie
N
Diez
Elisabeth
E
Gervois
Nadine
N
Jotereau
Francine
F
Quideau
Stéphane
S
D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000737:chemistry*; D002460:Cell Line; D002999:Clone Cells; D015195:Drug Design; D000939:Epitopes; D015789:HLA-A2 Antigen / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008024:Ligands; D058965:MART-1 Antigen; D008958:Models, Molecular; D018716:Molecular Mimicry; D009363:Neoplasm Proteins / Q000276:immunology; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry; D013329:Structure-Activity Relationship; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D000939:Epitopes; D015789:HLA-A2 Antigen; D008024:Ligands; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D009842:Oligopeptides; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma