Computer Modelling and Synthesis of Deoxy and Monohydroxy Analogues of a Ribitylaminouracil Bacterial Metabolite that Potently Activates Human T Cells.

5‐(2‐Oxopropylideneamino)‐6‐d‐ribitylaminouracil (5‐OP‐RU) is a natural product formed during bacterial synthesis of vitamin B2. It potently activates mucosal associated invariant T (MAIT) cells and has immunomodulatory, inflammatory, and anticancer properties. This highly polar and unstable compound forms a remarkably stable Schiff base with a lysine residue in major histocompatibility complex class I–related protein (MR1) expressed in antigen‐presenting cells. Inspired by the importance of the ribityl moiety of 5‐OP‐RU for binding to both MR1 and the T cell receptor (TCR) on MAIT cells, each OH was removed in silico. DFT calculations and MD simulations revealed a very stable hydrogen bond between the C3′−OH and uracil N1H, which profoundly restricts flexibility and positioning of each ribityl‐OH, potentially impacting their interactions with MR1 and TCR. By using deoxygenation strategies and kinetically controlled imine formation, four monodeoxyribityl and four monohydroxyalkyl analogues of 5‐OP‐RU were synthesised as new tools for probing T cell activation mechanisms. [ABSTRACT FROM AUTHOR]