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., 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.

Item ID: 62748
Item Type: Article (Research - C1)
ISSN: 1860-7187
Keywords: T-cell receptor; antigenic peptidomimetics; click chemistry; immunotherapy; organic haptens.
Copyright Information: © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Funders: Biotechnology and Biological Sciences Research Council (BBSRC), National Institute of General Medical Sciences (NIGMS), National Institutes of Health (NIH), MRC, Cardiff University (CU), National Health and Medical Research Council (NHMRC)
Projects and Grants: BBSRC grant BB/H001085/1, NIGMS R35 GM118166,, NHMRC CDF2 APP1131732
Date Deposited: 06 Aug 2020 05:34
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110799 Immunology not elsewhere classified @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920199 Clinical Health (Organs, Diseases and Abnormal Conditions) not elsewhere classified @ 100%
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