Mucosal-associated invariant T (MAIT) cells play a key role in antibacterial immunity as their membrane-bound T cell receptors (TCRs) recognize microbial antigens presented by surface proteins on antigen-presenting cells (APCs). The ligand-dependent activation of MAIT cells is mediated by the monomorphic MHC (major histocompatibility complex) class I-related (MR1) protein. MR1 binds the bacterial metabolite 5-OP-RU originating from the riboflavin biosynthesis and the resulting complex is presented on the surface of the APC, which leads to MAIT cell activation through formation of a ternary complex with their TCR receptor.[1] MAIT cells are considered to provide efficient protection against acute bacterial infections and seem to play crucial roles in other diseases, such as viral infections and cancer.[2]
However, medical application of natural MAIT modulators, such as 5-OP-RU and 5-A-RU, is limited by a short half-life time due to chemical instability. We aim to synthesize stabilized MAIT ligands as immunomodulators to utilize them in APC-targeted antibody-immunomodulator conjugates (AICs). Here, we report on the virtual in silico screening and chemical synthesis of the MAIT activators as well as preliminary immunological biological evaluation.
References
[1] A. Toubal et al., Nat. Rev. Immunol. 2019, 19, 643–657.
[2] J. Yan et al., Cancer Discov. 2020, 10, 124–141.