Poster Presentation CD1-MR1 2024

Development of lumazine analogues as MAIT cell activators (#103)

Shinsuke Inuki 1 , Ryosuke Takasaki 1 , Takuro Matsuoka 1 , Norihito Arichi 1 , Sho Yamasaki 2 , Hiroaki Ohno 1
  1. Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
  2. RIMD / IFReC, Osaka University, Suita, Osaka , Japan

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that are abundant in human tissues such as the gut, liver and peripheral blood. Upon infection with riboflavin-producing bacteria, MAIT cells are activated and produce inflammatory cytokines, which play an important role in biological defense against bacterial infection. MAIT cells are also implicated in various pathological conditions such as autoimmune diseases and cancer. Therefore, the modulation of MAIT cells has attracted attention as a therapeutic target for infectious diseases, cancer or autoimmune disorders.

MAIT cells are activated by recognizing small-molecule ligands presented by MR1 on antigen-presenting cells. 5-(2-Oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU) is a representative MR1 ligand, which shows potent MAIT cell activation by covalent bond formation between its iminoglyoxal group and Lys43 of MR1. However, 5-OP-RU is chemically unstable under physiological conditions because of the facile hydrolysis. Alternatively, an intramolecular condensation between the amino and carbonyl groups in 5-OP-RU provides the bicyclic compound, 7-methyl-8-D-ribityllumazine (RL-7-Me). RL-7-Me is chemically stable and has moderate activity toward MAIT cell activation although it lacks a Lys-reactive functional group.

We hypothesized that attaching a Lys-reactive group to bicyclic structures such as RL-7-Me would provide potent MAIT cell activators with chemical stability. In this study, we have investigated various bicyclic compounds bearing Lys-reactive groups and found chemically stable MAIT cell activators having a lumazine core and a 2-oxopropyl group as a Lys-reactive group. In this presentation, we will report the details of our research results, including the structure activity relationship study of lumazine analogues, evaluation of their activity toward MAIT cell and chemical stability.

  1. Godfrey, D. I.; Koay, H.-F.; McCluskey, J.; Gherardin, N. A. The Biology and Functional Importance of MAIT Cells. Nat. Immunol. 2019, 20, 1110–1128.
  2. Kjer-Nielsen, L.; Patel, O.; Corbett, A. J.; Le Nours, J.; Meehan, B.; Liu, L.; Bhati, M.; Chen, Z.; Kostenko, L.; Reantragoon, R.; Williamson, N. A.; Purcell, A. W.; Dudek, N. L.; McConville, M. J.; O’Hair, R. A. J.; Khairallah, G. N.; Godfrey, D. I.; Fairlie, D. P.; Rossjohn, J.; McCluskey, J. MR1 Presents Microbial Vitamin B Metabolites to MAIT Cells. Nature 2012, 491, 717–723.
  3. Corbett, A. J.; Eckle, S. B. G.; Birkinshaw, R. W.; Liu, L.; Patel, O.; Mahony, J.; Chen, Z.; Reantragoon, R.; Meehan, B.; Cao, H.; Williamson, N. A.; Strugnell, R. A.; Sinderen, D. V.; Mak, J. Y. W.; Fairlie, D. P.; Kjer-Nielsen, L.; Rossjohn, J.; McCluskey, J. T-Cell Activation by Transitory Neo-Antigens Derived from Distinct Microbial Pathways. Nature 2014, 509, 361–365.
  4. Mak, J. Y. W.; Xu, W.; Reid, R. C.; Corbett, A. J.; Meehan, B. S.; Wang, H.; Chen, Z.; Rossjohn, J.; McCluskey, J.; Liu, L.; Fairlie, D. P. Stabilizing short-lived Schiff base derivatives of 5-aminouracils that activate mucosal-associated invariant T cells. Nat. Commun. 2017, 8, 14599.