title: Covalent modification of a melanoma-derived antigenic peptide with a natural quinone methide. Preliminary chemical, molecular modelling and immunological evaluation studies.
abstract: A LigandFit shape-directed docking methodology was used to identify the best position at which the melanoma-derived MHC class-I HLA-A2-binding antigenic peptide ELAGIGILTV could be modified by attaching a small molecule capable of fitting at the interface of complementary determining regional (CDR) loops of a T-cell receptor (TCR) while triggering T-cell responses. The small molecule selected here for determining the feasibility of this alternative track to chemical alteration of antigenic peptides was the electrophilic quinone methide (+)-puupehenone (), a natural product that belongs to a family of marine metabolites capable of expressing immunomodulatory activities. A preliminary chemical reactivity model study revealed the efficacy of the thiol group of a cysteine (C) side-chain in its nucleophilic addition reaction with in a regio- and diastereoselective manner. The best TCR/HLA-A2 ligand [i.e., ELAGCGILTV-S-puupehenol ()] then identified by the LigandFit docking procedure was synthesized and used to pulse HLA-A2(+) T2 cells for T-cell stimulation. Among the ELAGIGILTV-specific T-cell clones we tested, five of them recognized the conjugate in spite of its low binding affinity for the HLA-A2 molecules. The resulting T-cell stimulation was determined through the intracytoplasmic secretion of IFN-gamma and the percentage of T-cells thus activated. These highly encouraging results indicate that small non-peptidic natural product-derived molecules attached onto the central part of an antigenic peptide can fit at the TCR/HLA-A2 interface with induction of T-cell responses.
authors.affiliation: Institut Européen de Chimie et Biologie, 2 rue Robert Escarpit, F-33607 Pessac Cedex, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Douat-Casassus
authors.forename: Nathalie
authors.initials: N
authors.lastname: Marchand-Geneste
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Diez
authors.forename: Céline
authors.initials: C
authors.lastname: Aznar
authors.forename: Philippe
authors.initials: P
authors.lastname: Picard
authors.forename: Serge
authors.initials: S
authors.lastname: Geoffre
authors.forename: Aline
authors.initials: A
authors.lastname: Huet
authors.forename: Marie-Lise
authors.initials: ML
authors.lastname: Bourguet-Kondracki
authors.forename: Nadine
authors.initials: N
authors.lastname: Gervois
authors.forename: Francine
authors.initials: F
authors.lastname: Jotereau
authors.forename: Stéphane
authors.initials: S
authors.lastname: Quideau
mesh_terms: D000939:Epitopes / Q000737:chemistry* / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000737:chemistry / Q000276:immunology; D006801:Humans; D045563:Indolequinones / Q000737:chemistry* / Q000276:immunology*; D008545:Melanoma / Q000276:immunology*; D008954:Models, Biological; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000939:Epitopes; D015789:HLA-A2 Antigen; D045563:Indolequinones; D010455:Peptides; C068040:quinone methide