Development of Ribityllumazine\nAnalogue as Mucosal-Associated\nInvariant T Cell Ligands

Mucosal-associated invariant T (MAIT) cells are a subset\nof innate-like\nT cells abundant in human tissues that play a significant role in\ndefense against bacterial and viral infections and in tissue repair.\nMAIT cells are activated by recognizing microbial-derived small-molecule\nligands presented by the MHC class I related-1 protein. Although several\nMAIT cell modulators have been identified in the past decade, potent\nand chemically stable ligands remain limited. Herein, we carried out\na structure–activity relationship study of ribityllumazine\nderivatives and found a chemically stable MAIT cell ligand with a\npteridine core and a 2-oxopropyl group as the Lys-reactive group.\nThe ligand showed high potency in a cocultivation assay using model\ncell lines of antigen-presenting cells and MAIT cells. The X-ray crystallographic\nanalysis revealed the binding mode of the ligand to MR1 and the T\ncell receptor, indicating that it forms a covalent bond with MR1 via\nSchiff base formation. Furthermore, we found that the ligand stimulated\nproliferation of human MAIT cells in human peripheral blood mononuclear\ncells and showed an adjuvant effect in mice. Our developed ligand\nis one of the most potent among chemically stable MAIT cell ligands,\ncontributing to accelerating therapeutic applications of MAIT cells.