A phospholipid mimetic targeting LRH-1 ameliorates colitis. Issue 7 (21st July 2022)

• Record Type: Journal Article
• Authors: Mays, Suzanne G.; D'Agostino, Emma H.; Flynn, Autumn R.; Huang, Xiangsheng; Wang, Guohui; Liu, Xu; Millings, Elizabeth J.; Okafor, C. Denise; Patel, Anamika; Cato, Michael L.; Cornelison, Jeffery L.; Melchers, Diana; Houtman, René; Moore, David D.; Calvert, John W.; Jui, Nathan T.; Ortlund, Eric A.
• Is Part Of: Cell chemical biology. Volume 29:Issue 7(2022)
• Page Start: 1174
• Page End: 1186.e7
• Publication Date: 2022-07-21
• Subjects: phospholipid -- LRH-1 -- nuclear receptor -- agonist -- ulcerative colitis -- liver -- x-ray crystallography -- coregulator; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2022.03.001
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical abstract: Highlights: Phospholipid (PL) mimics contain features of synthetic and PL LRH-1 agonists Interactions made by the PL-mimicking group improve binding affinity and LRH-1 activity 10CA reduces the expression of lipogenic genes in mouse liver 10CA reduces inflammation and disease severity in a mouse model of ulcerative colitis Abstract : Mays and D'Agostino et al. show that combining features of synthetic and phospholipid agonists improves LRH-1 activation. Interactions made by the PL-mimicking group of 10CA (purple) stimulate LRH-1 transcriptional activity and promote coregulator recruitment. 10CA upregulates anti-inflammatory genes in the gut and is efficacious in a mouse model of colitis.