Covalent modification of a melanoma-derived antigenic peptide with a natural quinone methide. Preliminary chemical, molecular modelling and immunological evaluation studies{ - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Molecular BioSystems Année : 2006

Covalent modification of a melanoma-derived antigenic peptide with a natural quinone methide. Preliminary chemical, molecular modelling and immunological evaluation studies{

Résumé

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 (1), 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 1 in a regio- and diastereoselective manner. The best TCR/HLA-A2 ligand [i.e., ELAGCGILTVS- puupehenol (4b)] 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 4b 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-c 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.
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Dates et versions

hal-00084586 , version 1 (07-07-2006)

Identifiants

  • HAL Id : hal-00084586 , version 1

Citer

Céline Douat-Casassus, Nathalie Geneste, Elisabeth Diez, Céline Aznar, Philippe Picard, et al.. Covalent modification of a melanoma-derived antigenic peptide with a natural quinone methide. Preliminary chemical, molecular modelling and immunological evaluation studies{. Molecular BioSystems, 2006, 2, pp.240-249. ⟨hal-00084586⟩

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