Language
English
Publication Date
7-21-2022
Journal
Cell Chemical Biology
DOI
10.1016/j.chembiol.2022.03.001
PMID
35316658
PMCID
PMC11288311
PubMedCentral® Posted Date
7-30-2024
PubMedCentral® Full Text Version
Author MSS
Abstract
Phospholipids are ligands for nuclear hormone receptors (NRs) that regulate transcriptional programs relevant to normal physiology and disease. Here, we demonstrate that mimicking phospholipid-NR interactions is a robust strategy to improve agonists of liver receptor homolog-1 (LRH-1), a therapeutic target for colitis. Conventional LRH-1 modulators only partially occupy the binding pocket, leaving vacant a region important for phospholipid binding and allostery. Therefore, we constructed a set of molecules with elements of natural phospholipids appended to a synthetic LRH-1 agonist. We show that the phospholipid-mimicking groups interact with the targeted residues in crystal structures and improve binding affinity, LRH-1 transcriptional activity, and conformational changes at a key allosteric site. The best phospholipid mimetic markedly improves colonic histopathology and disease-related weight loss in a murine T cell transfer model of colitis. This evidence of in vivo efficacy for an LRH-1 modulator in colitis represents a leap forward in agonist development.
Keywords
Animals, Colitis, Ligands, Mice, Phospholipids, Receptors, Cytoplasmic and Nuclear, Phospholipid, LRH-1, nuclear receptor, agonist, ulcerative colitis
Published Open-Access
yes
Recommended Citation
Mays, Suzanne G; D'Agostino, Emma H; Flynn, Autumn R; et al., "A Phospholipid Mimetic Targeting LRH-1 Ameliorates Colitis" (2022). Faculty and Staff Publications. 3291.
https://digitalcommons.library.tmc.edu/baylor_docs/3291
Included in
Digestive System Diseases Commons, Gastroenterology Commons, Hepatology Commons, Medical Sciences Commons, Pediatrics Commons