The Chemical Synthesis, Stability, and Activity of MAIT Cell Prodrug Agonists That Access MR1 in Recycling Endosomes

ACS Chem Biol. 2020 Feb 21;15(2):437-445. doi: 10.1021/acschembio.9b00902. Epub 2020 Jan 14.

Abstract

Mucosal-associated invariant T (MAIT) cells are antibacterial effector T cells that react to pyrimidines derived from bacterial riboflavin synthesis presented by the monomorphic molecule MR1. A major challenge in MAIT cell research is that the commonly used MAIT agonist precursor, 5-amino-6-d-ribitylaminouracil (5-A-RU), is labile to autoxidation, resulting in a loss of biological activity. Here, we characterize two independent autoxidation processes by LCMS. To overcome the marked instability, we report the synthesis of a 5-A-RU prodrug generated by modification of the 5-amino group with a cleavable valine-citrulline-p-aminobenzyl carbamate. The compound is stable in prodrug form, with the parent amine (i.e., 5-A-RU) released only after enzymatic cleavage. Analysis of the prodrug in vitro and in vivo showed an enhanced MAIT cell activation profile compared to 5-A-RU, which was associated with preferential loading within recycling endosomes, a route used by some natural agonists. This prodrug design therefore overcomes the difficulties associated with 5-A-RU in biological studies and provides an opportunity to explore different presentation pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Endosomes / metabolism*
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Immunologic Factors / chemical synthesis
  • Immunologic Factors / metabolism
  • Immunologic Factors / pharmacology*
  • Lymphocyte Activation / drug effects*
  • Mice
  • Minor Histocompatibility Antigens / metabolism*
  • Mucosal-Associated Invariant T Cells / drug effects*
  • Prodrugs / chemical synthesis
  • Prodrugs / metabolism
  • Prodrugs / pharmacology*
  • Ribitol / analogs & derivatives
  • Ribitol / chemical synthesis
  • Ribitol / metabolism
  • Ribitol / pharmacology
  • Uracil / analogs & derivatives
  • Uracil / chemical synthesis
  • Uracil / metabolism
  • Uracil / pharmacology

Substances

  • 5-amino-6-D-ribitylaminouracil
  • Histocompatibility Antigens Class I
  • Immunologic Factors
  • MR1 protein, human
  • Minor Histocompatibility Antigens
  • Mr1 protein, mouse
  • Prodrugs
  • Ribitol
  • Uracil