Synthesis and biological evaluation of hapten-clicked analogues of the antigenic peptide Melan-A/MART-126(27L)-35.

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-1 26(27L)-35 antigenic peptide ELAGIGILTV. The Cu(I)-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 those 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 modifications of the N - and C -termini of this agonist, which was intended to enhance HLA-A2 binding, one of the resulting 7 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-1 26-35 peptide to cross-react with peptidomimetics bearing organic motifs structurally different from the native central amino acids.