ATLANTA — Two structurally modified compounds derived from an anti-inflammatory metabolite demonstrated enhanced anti-inflammatory activity in experimental ulcerative colitis in mice and human tissue, offering an underexplored drug discovery opportunity for this chronic inflammatory disease, according to a study led by researchers in the Institute for Biomedical Sciences at Georgia State University.
The findings, published in the International Journal of Molecular Sciences, suggest that two selected compounds, MLY2 and MLY8, improved multiple measures of disease activity in experimental colitis in mice, including restoration of colon length and reduction of fecal lipocalin-2 (a biomarker of intestinal inflammation). Notably, in laboratory-cultured colon tissue samples from patients with treatment-refractory ulcerative colitis, both compounds suppressed inflammatory cytokine production more effectively than M13, the study's lead metabolite, supporting further preclinical investigations of MLY2 and MLY8.
Ulcerative colitis, a chronic inflammatory disease of the gastrointestinal tract, remains a major clinical challenge because of the limited availability of safe, orally active anti-inflammatory drugs. Despite major advances in therapies, a considerable proportion of patients fail to achieve sustained remission or experience loss of response over time, highlighting the need for safer and more effective anti-inflammatory drug candidates.
Phase II metabolism is traditionally viewed as a detoxification and deactivation process, but emerging evidence suggests that certain metabolites retain or exhibit enhanced pharmacological activity, offering an underexplored drug discovery opportunity. M13 was previously identified as a biologically active metabolite (a compound produced during metabolism) with enhanced anti-inflammatory activity and improved biopharmaceutical properties compared with its parent compound, 6-shogaol, suggesting that metabolites can provide valuable starting points for identifying new biologically active compounds.
In this study, the researchers investigated whether phase II metabolites could serve as chemically productive scaffolds for drug discovery and if selective editing of the glutathione tripeptide sequence could improve anti-inflammatory activity and generate anti-inflammatory leads with improved biological activity. Using M13 as the lead structure for medicinal chemistry optimization, MLY2 and MLY8 were evaluated in dextran sulfate sodium-induced experimental colitis in mice, laboratory-cultured colon tissue samples from patients with treatment-refractory ulcerative colitis and preliminary safety and tolerability studies.
"This work shows that modifying the chemical structure of a biologically active phase II metabolite can be a productive strategy for discovering new anti-inflammatory drug candidates," said Chunhua Yang, senior author of the study and a research assistant professor in the Institute for Biomedical Sciences at Georgia State. "The findings provide a foundation for follow-up studies, suggesting that biologically active phase II metabolites may represent underutilized scaffolds for medicinal chemistry optimization in inflammatory disease."
The study was funded by the Georgia State University Research Foundation: Faculty Internal Grant and the Georgia State University Research Foundation: Advancing Research Innovation and Scholarly Excellence (ARISE) Challenge Award.
Additional authors of the study include Xiaodi Shi, Rabeya Jafrin Mow, Dingpei Long, Xiaomeng Shi and Pallavi Garg of the Institute for Biomedical Sciences at Georgia State; Olivier Merlin-Zhang and Emma Xu of Wake Forest University; and Shanthi Srinivasan of Emory University School of Medicine and Atlanta Veterans Affairs Medical Center.
To read the study, visit https://www.mdpi.com/1422-0067/27/18/8285 .
