Covalent modification of a melanoma-derived antigenic peptide with a natural quinone methide. Preliminary chemical, molecular modelling and immunological evaluation studies.
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.
Douat-Casassus
Céline
C
Institut Européen de Chimie et Biologie, 2 rue Robert Escarpit, F-33607 Pessac Cedex, France.
Marchand-Geneste
Nathalie
N
Diez
Elisabeth
E
Aznar
Céline
C
Picard
Philippe
P
Geoffre
Serge
S
Huet
Aline
A
Bourguet-Kondracki
Marie-Lise
ML
Gervois
Nadine
N
Jotereau
Francine
F
Quideau
Stéphane
S
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
D000939:Epitopes; D015789:HLA-A2 Antigen; D045563:Indolequinones; D010455:Peptides; C068040:quinone methide