{
  "abstract": "Mucosal‐associated invariant T cells (MAIT cells) are innate‐like immune cells (T lymphocytes) that protect against bacterial infections. They are potently activated by the microbial metabolite 5‐(2‐oxopropylideneamino)‐d‐ribitylaminouracil (5‐OP‐RU), which bonds covalently to an amine of a specific lysine residue of the antigen‐presenting protein MR1 to form an imine (Schiff base). However, 5‐OP‐RU undergoes rapid degradative intramolecular cyclisation in water, and more robust analogues are needed for therapeutic applications. Here, inspired by the structural similarities between 5‐OP‐RU and 6‐formylpterin, a water‐stable covalent MR1 ligand that does not activate MAIT cells, we describe the design and synthesis of a novel isopterin analogue of this microbial natural product, and show that it is both water‐stable and activates reporter cells expressing the MAIT T cell receptor. Further, we present a protein‐bound crystal structure and molecular dynamics simulations of this stable analogue to show that it mimics the MR1‐bound conformation of 5‐OP‐RU. This study demonstrates the potential of this bicyclic scaffold for stabilising 5‐OP‐RU mimetics, advances our understanding of the molecular requirements for MR1 binding and MAIT cell activation, and informs the design and synthesis of future MAIT cell antigens as potential immunotherapeutics.",
  "abstract_shown": true,
  "affiliations": [
    "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",
    "Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute Monash University Clayton Victoria Australia",
    "Department of Microbiology and Immunology The University of Melbourne, at the Peter Doherty Institute For Infection and Immunity Melbourne Victoria Australia"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Jeffrey Y. W. Mak",
      "orcid": "0000-0002-8011-4539"
    },
    {
      "affs": [
        0
      ],
      "name": "Huy N. Hoang"
    },
    {
      "affs": [
        1
      ],
      "name": "Wael Awad",
      "orcid": "0000-0002-7597-2133"
    },
    {
      "affs": [
        2
      ],
      "name": "Xin Yi Lim",
      "orcid": "0000-0002-9806-5894"
    },
    {
      "affs": [
        0
      ],
      "name": "Damica D. Laurie",
      "orcid": "0009-0005-9992-3108"
    },
    {
      "affs": [
        0
      ],
      "name": "Ryan J. D. Rivero",
      "orcid": "0000-0001-5009-3469"
    },
    {
      "affs": [
        2
      ],
      "name": "James McCluskey",
      "orcid": "0000-0002-8597-815X"
    },
    {
      "affs": [
        2
      ],
      "name": "Alexandra J. Corbett",
      "orcid": "0000-0003-1618-4337"
    },
    {
      "affs": [
        1
      ],
      "name": "Jamie Rossjohn"
    },
    {
      "affs": [
        0
      ],
      "name": "David P. Fairlie",
      "orcid": "0000-0002-7856-8566"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/adn6v0t2ay3ma.bib",
  "cited_by": 0,
  "doi": "10.1002/chem.71494",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13729931/",
  "id": "adn6v0t2ay3ma",
  "issns": [
    "0947-6539",
    "1521-3765"
  ],
  "landing_url": "https://doi.org/10.1002/chem.71494",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research Article"
    ],
    [
      "openalex",
      "2403|Immunotherapy and Immune Responses"
    ]
  ],
  "openalex": "W7203500288",
  "pdf_url": null,
  "pmcid": "PMC13729931",
  "pmid": "42599025",
  "published": "2026-08-14",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/adn6v0t2ay3ma.ris",
  "sources": [
    {
      "first_seen": "2026-11-07T12:22:39Z",
      "native_id": "PMC13729931",
      "source": "pmc",
      "url": "https://doi.org/10.1002/chem.71494"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|Immunotherapy and Immune Responses",
      "subfield": "immunology"
    }
  ],
  "title": "A Stable Isopterin Mimic of a Potent Bacterial Stimulant of T Cells",
  "title_text": "A Stable Isopterin Mimic of a Potent Bacterial Stimulant of T Cells",
  "type": "peer-reviewed",
  "updated_at": "2026-11-07T12:22:39Z",
  "url": "https://research.draconitic.com/paper/adn6v0t2ay3ma",
  "venue": "Chemistry (Weinheim an Der Bergstrasse, Germany)",
  "versions": []
}