{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:03:33Z","timestamp":1792789413398,"version":"4.5.0"},"reference-count":42,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Georgia State University Research Foundation","award":["RS00020298"],"award-info":[{"award-number":["RS00020298"]}],"id":[{"id":"https:\/\/ror.org\/03qt6ba18","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Georgia State University Research Foundation","award":["RS00020301"],"award-info":[{"award-number":["RS00020301"]}],"id":[{"id":"https:\/\/ror.org\/03qt6ba18","id-type":"ROR","asserted-by":"crossref"}]},{"award":["RS00020298"],"award-info":[{"award-number":["RS00020298"]}],"id":[{"id":"https:\/\/ror.org\/03qt6ba18","id-type":"ROR","asserted-by":"publisher"}]},{"award":["RS00020301"],"award-info":[{"award-number":["RS00020301"]}],"id":[{"id":"https:\/\/ror.org\/03qt6ba18","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>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-\u03baB (NF-\u03baB) 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.<\/jats:p>","DOI":"10.3390\/ijms27188285","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T12:50:58Z","timestamp":1790859058000},"page":"8285","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Phase II Metabolite-Inspired Tripeptide Editing Generates Anti-Inflammatory Candidates for Treatment-Refractory Ulcerative Colitis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-3170-3029","authenticated-orcid":false,"given":"Xiaodi","family":"Shi","sequence":"first","affiliation":[{"name":"Digestive Disease Research Group, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, 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