Tarbe, Marion, Miles, John J., Edwards, Emily S. J., Miles, Kim M., Sewell, Andrew K., Baker, Brian M., and Quideau, Stéphane (2020) Synthesis and biological evaluation of hapten-clicked analogues of the antigenic peptide Melan-A/MART-1₂₆₍₂₇L₎₋₃₅. ChemMedChem, 15 (9). pp. 799-807.

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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 Cu¹ -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-12₂₆₋₃₅ peptide to cross-react with peptidomimetics bearing organic motifs structurally different from the native central amino acids.

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