Oral Presentation Royal Australian Chemical Institute National Congress 2026

Stress-related heterobicyclo[3.3.1]nonane adduct potently activates tumor-reactive T cells (136938)

Damica D Laurie 1 , Ryan JD Rivero 1 , Songyi Li 2 , Ching-Seng Ang 3 , Michael NT Souter 2 , Zhenjun Chen 2 , James McCluskey 2 , David P Fairlie 1 , Jeffrey YW Mak 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. Bio21 Mass Spectrometry and Proteomics Facility, The University of Melbourne, Parkville, Victoria, Australia

The immunological protein MR1 is unique in its ability to bind and present heterocyclic small molecules to activate T cells.1 For example, the uracil analogue 5‑OP‑RU, a condensation product of the metabolite glyoxal with an intermediate of riboflavin biosynthesis, potently activates T cells to drive antibacterial and antiviral immunity, tissue repair, and protection against tumours.1 However, whether other heterocyclic adducts from endogenous metabolic pathways can form MR1 ligands that activate T cells is less well understood. Here, we describe the new MR1 ligand M3Ade, an adduct of adenine and malondialdehyde, the latter being a marker2 of metabolic stress associated with cancer in mammals. Here we describe the structural elucidation of its heterobicyclo[3.3.1]nonane core by NMR spectroscopy and DFT calculations, and propose a mechanism for its formation. Although M3Ade is likely generated as a racemate3 in vivo, chiral separation demonstrated that only one enantiomer potently activated tumour-reactive T cells. Lastly, we describe our efforts towards an asymmetric synthesis of M3Ade to confirm the identity of the bioactive enantiomer, enable analogue development, and support comprehensive in vitro and in vivo characterisation. Diastereoselective bridgehead installation via chiral auxiliary–controlled cuprate addition, followed by a substrate-controlled ring closure, gave an advanced intermediate highly analogous to M3Ade. This work expands the understanding of how certain immune cells detect chemical signatures of danger, and may support development of future therapeutics.

  1. Mak, J. Y. W. et al. Chemical modulators of mucosal associated invariant T cells. Acc Chem Res 2021, 54, 3462.
  2. Moldogazieva, N. T. et al. Lipid peroxidation: Reactive carbonyl species, protein/DNA adducts, and signaling switches in oxidative stress and cancer. Biochem Biophys Res Commun 2023, 687, 149167.
  3. Bitchagno, G. T. M. et al. Demystifying racemic natural products in the homochiral world. Nat Rev Chem 2022, 6, 806.