Skip to Main content Skip to Navigation
Journal articles

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.
Document type :
Journal articles
Complete list of metadata

https://www.hal.inserm.fr/inserm-03349333
Contributor : Nadine Gervois Connect in order to contact the contributor
Submitted on : Monday, September 20, 2021 - 2:32:33 PM
Last modification on : Wednesday, September 22, 2021 - 3:24:33 AM
Long-term archiving on: : Tuesday, December 21, 2021 - 6:52:59 PM

File

 Restricted access
To satisfy the distribution rights of the publisher, the document is embargoed until : jamais

Please log in to resquest access to the document

Identifiers

Collections

Citation

Céline Douat-Casassus, Nathalie Marchand-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, Royal Society of Chemistry, 2006, 2 (5), pp.240. ⟨10.1039/b518044a⟩. ⟨inserm-03349333⟩

Share

Metrics

Les métriques sont temporairement indisponibles