Development of Ribityllumazine Analogs as Mucosal-associated Invariant T Cell Activators

Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T cells abundant in human tissues that play a significant role in defense against bacterial and viral infections and in tissue repair. MAIT cells are activated by recognizing microbial-derived small-molecule ligands presented by the MHC class I related-1 protein. Although several MAIT cell modulators have been identified in the last decade, potent and chemically stable ligands remain limited. Herein, we carried out a structure-activity relationship study of ribityllumazine derivatives and found chemically stable MAIT cell activators with a pteridine core and a 2-oxopropyl group as the Lys-reactive group. The activators showed high potency toward a co-cultivation assay using model cell lines of antigen-presenting cells and MAIT cells (EC50 = 20 nM). The X-ray crystallographic analysis revealed the binding mode of the activator to MR1 and T cell receptor, indicating that it forms a covalent bond with MR1 via Shiff base formation. Furthermore, we found that one activator stimulated proliferation of human MAIT cells in human peripheral blood mononuclear cells and showed an adjuvant effect in mice. Our developed activator is one of the most potent among chemically stable MAIT cell activators, contributing to accelerating therapeutic applications of MAIT cells.