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Synthesis and study of compounds able to activate MAIT cells

Abstract : MAIT cells are innate-like T lymphocytes that recognize a series of microbial antigens derived from the riboflavin (vitamin B2) biosynthesis pathway, which are exclusively present in bacteria and some yeasts. The TCR dependent activation of MAIT cells requires an antigenic presentation mediated by MR1 (MHC-class I related protein) expressed mostly by antigen presenting cells (APCs). Once activated, MAIT cells can exert antimicrobial functions notably by killing pathogen-infected cells. This antimicrobial activity suggest a strong therapeutic interest in targeting MAIT cells in innovative antimicrobial immunotherapies. Unfortunately, the most active antigen discovered yet named 5-OP-RU suffers from a high chemical instability, thus making difficult the study of MAIT cell biology. 5-OP-RU is produced from a condensation reaction between its chemical precursor 5-A-RU (also unstable) and endogenous methylglyoxal. To overcome the stability issues, we designed and synthetized stable analogues of MAIT cells trying to maintain a strong potency of MAIT cells activation. We also synthetized prodrugs of 5-A-RU that were able of releasing the molecule in situ to form 5-OP-RU directly in APCs. Finally, we developed a new clickable analogue of 5-OP-RU that can be used to track and visualize MAIT cell antigens in biological tissues and cells by fluorescence microscopy.
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https://tel.archives-ouvertes.fr/tel-03200069
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Submitted on : Friday, April 16, 2021 - 10:57:07 AM
Last modification on : Monday, April 19, 2021 - 11:53:50 AM

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  • HAL Id : tel-03200069, version 1

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Thomas Yvorra. Synthesis and study of compounds able to activate MAIT cells. Medicinal Chemistry. Université Paris sciences et lettres, 2020. English. ⟨NNT : 2020UPSLT011⟩. ⟨tel-03200069⟩

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