Synthesis and Biological Evaluation of Hapten-Clicked Analogues of The Antigenic Peptide Melan-A/MART-126(27L)-35

Marion Tarbe, John J. Miles, Emily S.J. Edwards, Kim M. Miles, Andrew K. Sewell, Brian M. Baker, Stéphane Quideau

Research output: Contribution to journalArticleResearchpeer-review

Abstract

A click-chemistry-based approach was implemented to prepare peptidomimetics designed in silico and made from aromatic azides and a propargylated GIGI-mimicking platform derived from the altered Melan-A/MART-126(27L)-35 antigenic peptide ELAGIGILTV. The CuI-catalyzed Huisgen cycloaddition was carried out on solid support to generate rapidly a first series of peptidomimetics, which were evaluated for their capacity to dock at the interface between the major histocompatibility complex class-I (MHC-I) human leucocyte antigen (HLA)-A2 and T-cell receptors (TCRs). Despite being a weak HLA-A2 ligand, one of these 11 first synthetic compounds bearing a p-nitrobenzyl-triazole side chain was recognized by the receptor proteins of Melan-A/MART-1-specific T-cells. After modification of the N and C termini of this agonist, which was intended to enhance HLA-A2 binding, one of the resulting seven additional compounds triggered significant T-cell responses. Thus, these results highlight the capacity of naturally circulating human TCRs that are specific for the native Melan-A/MART-126-35 peptide to cross-react with peptidomimetics bearing organic motifs structurally different from the native central amino acids.

Original languageEnglish
Pages (from-to)799-807
Number of pages9
JournalChemMedChem
Volume15
Issue number9
DOIs
Publication statusPublished - 6 May 2020

Keywords

  • antigenic peptidomimetics
  • click chemistry
  • immunotherapy
  • organic haptens
  • T-cell receptor

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