A phospholipid mimetic targeting LRH-1 ameliorates colitis

Suzanne G. Mays, Emma H. D'Agostino, Autumn R. Flynn, Xiangsheng Huang, Guohui Wang, Xu Liu, Elizabeth J. Millings, C. Denise Okafor, Anamika Patel, Michael L. Cato, Jeffery L. Cornelison, Diana Melchers, René Houtman, David D. Moore, John W. Calvert, Nathan T. Jui, Eric A. Ortlund

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1174-1186.e7
JournalCell Chemical Biology
Issue number7
StatePublished - Jul 21 2022

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry


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