{
  "abstract": "Ulcerative colitis remains a major clinical challenge due to limited availability of safe, orally active anti-inflammatory drugs. Although phase II metabolism is traditionally viewed as a detoxification process, certain metabolites retain or exhibit enhanced pharmacological activity, offering an underexplored drug discovery opportunity. Here, we investigated phase II metabolite-inspired tripeptide editing using M13, a glutathione-conjugated metabolite of the anti-inflammatory natural product 6-shogaol, as a lead scaffold. A focused library of 38 analogs was generated by systematic tripeptide editing while preserving the central cysteine-containing 6-shogaol-derived scaffold. Phenotypic nuclear factor-κB (NF-κB) reporter screening identified 29 of 38 analogs with greater inhibitory activity than M13 at the screening concentration. Two selected leads, MLY2 and MLY8, demonstrated enhanced anti-inflammatory activity in Dextran Sulfate Sodium-induced experimental colitis, including restoration of colon length and reductions in fecal lipocalin-2 and pro-inflammatory cytokines. Both compounds also suppressed inflammatory cytokine production more effectively than M13 in ex vivo colonic biopsies from patients with treatment-refractory ulcerative colitis. In parallel, MLY2 and MLY8 showed no detectable mutagenicity under the Ames assay conditions and were well tolerated in a preliminary single-dose maximum tolerated dose study. Collectively, these findings establish phase II metabolite-inspired tripeptide editing as a productive lead-discovery strategy and identify MLY2 and MLY8 as anti-inflammatory leads warranting further preclinical characterization.",
  "abstract_shown": true,
  "affiliations": [
    "Digestive Disease Research Group, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA",
    "School of Medicine, Wake Forest University, Winston-Salem, NC 27101, USA",
    "Division of Digestive Diseases, Emory University School of Medicine, Atlanta, GA 30307, USA",
    "Atlanta Veterans Affairs Medical Center, Decatur, GA 30302, USA"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Xiaodi Shi",
      "orcid": "0009-0005-3170-3029"
    },
    {
      "affs": [
        0
      ],
      "name": "Rabeya Jafrin Mow",
      "orcid": "0009-0004-2068-7759"
    },
    {
      "affs": [
        0
      ],
      "name": "Dingpei Long",
      "orcid": "0000-0002-2907-6901"
    },
    {
      "affs": [
        1
      ],
      "name": "Olivier Merlin-Zhang"
    },
    {
      "affs": [
        1
      ],
      "name": "Emma Xu"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiaomeng Shi"
    },
    {
      "affs": [
        0
      ],
      "name": "Pallavi Garg"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Shanthi Srinivasan"
    },
    {
      "affs": [
        0
      ],
      "name": "Chunhua Yang",
      "orcid": "0000-0003-0805-1008"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/eshm9em5by6ck.bib",
  "cited_by": 0,
  "doi": "10.3390/ijms27188285",
  "fulltext_url": null,
  "id": "eshm9em5by6ck",
  "issns": [
    "1422-0067"
  ],
  "landing_url": "https://www.mdpi.com/1422-0067/27/18/8285",
  "language": null,
  "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": [
    [
      "openalex",
      "1311|Inflammatory Bowel Disease"
    ]
  ],
  "openalex": "W7214477420",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-17",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/eshm9em5by6ck.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:55Z",
      "native_id": "10.3390/ijms27188285",
      "source": "crossref",
      "url": "https://www.mdpi.com/1422-0067/27/18/8285"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:1311|Inflammatory Bowel Disease",
      "subfield": "genetics-genomics"
    }
  ],
  "title": "Phase II Metabolite-Inspired Tripeptide Editing Generates Anti-Inflammatory Candidates for Treatment-Refractory Ulcerative Colitis",
  "title_text": "Phase II Metabolite-Inspired Tripeptide Editing Generates Anti-Inflammatory Candidates for Treatment-Refractory Ulcerative Colitis",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:18:55Z",
  "url": "https://research.draconitic.com/paper/eshm9em5by6ck",
  "venue": "International Journal of Molecular Sciences",
  "versions": []
}