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

Tarbe, Marion, Miles, John J., Edwards, Emily S. J., Sewell, Andrew K. ORCID: https://orcid.org/0000-0003-3194-3135, 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. 10.1002/cmdc.202000038

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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‐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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Wiley
ISSN:	1860-7179
Date of First Compliant Deposit:	3 April 2020
Date of Acceptance:	11 March 2020
Last Modified:	04 Dec 2024 15:45
URI:	https://orca.cardiff.ac.uk/id/eprint/130749

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