Oral Presentation Royal Australian Chemical Institute National Congress 2026

Potent immunomodulators developed from an unstable microbial metabolite (136446)

Jeffrey YW Mak 1 , Ryan JD Rivero 1 , Huy N Hoang 1 , Xin Yi Lim 2 , Wael Awad 3 , Jieru Deng 2 , Damica D Laurie 1 , Hamish EG McWilliam 2 , Jose A Villadangos 2 , James McCluskey 2 , Alexandra J Corbett 2 , Jamie Rossjohn 3 , David P Fairlie 1
  1. Centre for Chemistry and Drug Discovery and ARC Centre of Excellence for Innovations in Peptide and Protein Science, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
  2. Department of Microbiology & Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
  3. Infection and Immunity Program & Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia

Keywords: covalent ligands, immunology, biological activity, natural products, chemical tools

 

Vitamin B2 biosynthesis, a process that takes place in many microbes but not in mammals, produces molecules that are detected as chemical signatures of infection. In particular, the biosynthetic by-product named 5-OP-RU activates an abundant population of immune cells known as mucosal associated invariant T cells (MAIT cells) with exquisite potency (EC50 2 pM).1,2 It covalently binds its target protein MR1 to activate MAIT cells, which confers protection against viral and bacterial infections, promotes wound healing, and protects mice against tumours.3 However, its considerable instability (half-life 88 min) severely limits the study of MAIT cells and the development of MAIT-dependent medicines.2 Here, we develop a suite of new stable analogues, including one that most faithfully mimics the protein-bound conformation of 5-OP-RU,4 best-in-class stimulators and inhibitors of MAIT cell activation, and diversely labelled protein-pulldown and fluorescent tools for studying MR1.5 Computer modelling casts new light on the molecular mechanism of MAIT cell activation, revealing that agonists are first captured in a MR1 cleft via pi-interactions and H-bonds, before more tightly attaching via a covalent bond to Lys43.5 We describe the synthesis and properties of these functionality-rich molecules to advance our understanding of the molecular mechanisms of MR1- and MAIT-based immunity, and to help realise new immunotherapeutics, vaccines and anticancer drugs.

  1. Corbett, A. J. et al. T-cell activation by transitory neo-antigens derived from distinct microbial pathways. Nature 2014, 509, 361.
  2. Mak, J. Y. W. et al. Stabilizing short-lived Schiff base derivatives of 5-aminouracils that activate mucosal-associated invariant T cells. Nat. Commun. 2017, 8, 14599.
  3. Mak, J. Y. W. et al. Chemical modulators of mucosal associated invariant T cells. Acc. Chem. Res. 2021, 54, 3462.
  4. Mak, J. Y. W. et al. A Stable Isopterin Mimic of a Potent Bacterial Stimulant of T cells. Submitted 2026.
  5. Mak, J. Y. W. et al. Potent Immunomodulators Developed from an Unstable Bacterial Metabolite of Vitamin B2 Biosynthesis. Angew. Chem. Int. Ed. 2024, 63, e202400632.