Researchers at Georgia State University identified two metabolite-inspired compounds that showed enhanced anti-inflammatory activity in experimental models of ulcerative colitis, potentially opening a new avenue for developing treatments for this chronic inflammatory disease.
The study, published in the International Journal of Molecular Sciences, evaluated compounds MLY2 and MLY8, which were developed through structural modifications of an anti-inflammatory metabolite known as M13. Both compounds improved multiple measures of disease activity in a mouse model of experimental colitis, including restoration of colon length and reductions in fecal lipocalin-2, a biomarker associated with intestinal inflammation.
Researchers also tested the compounds using laboratory-cultured colon tissue obtained from patients with treatment-refractory ulcerative colitis. MLY2 and MLY8 suppressed inflammatory cytokine production more effectively than M13, supporting further preclinical investigation of the compounds as potential anti-inflammatory drug candidates.
Ulcerative colitis is a chronic inflammatory disease affecting the gastrointestinal tract. While treatment options have expanded, some patients do not achieve sustained remission or lose their response to existing therapies over time, creating continued demand for additional safe and effective anti-inflammatory treatments.
The research examines an unconventional approach to drug discovery centered on phase II metabolites. These metabolites have traditionally been viewed primarily as products of detoxification and drug deactivation, but emerging research indicates that some can retain or even demonstrate enhanced biological activity.
M13 had previously been identified as a biologically active metabolite with stronger anti-inflammatory activity and improved biopharmaceutical properties compared with its parent compound, 6-shogaol. Researchers used M13 as the starting structure for medicinal chemistry optimization, selectively modifying its glutathione tripeptide sequence to determine whether they could generate compounds with greater biological activity.
MLY2 and MLY8 were subsequently evaluated in dextran sulfate sodium-induced colitis in mice, human colon tissue samples from patients with treatment-refractory ulcerative colitis, and preliminary safety and tolerability studies. The findings suggest biologically active metabolites could serve as underused starting points for developing new drugs targeting inflammatory diseases.
The research was supported by the Georgia State University Research Foundation through a Faculty Internal Grant and an Advancing Research Innovation and Scholarly Excellence Challenge Award. Researchers from Wake Forest University, Emory University School of Medicine, and the Atlanta Veterans Affairs Medical Center also contributed to the study.
KEY QUOTE:
“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. 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.”
Chunhua Yang, Research Assistant Professor At The Institute For Biomedical Sciences At Georgia State University
