A phospholipid mimetic targeting LRH-1 ameliorates colitis

Cell Chem Biol. 2022 Jul 21;29(7):1174-1186.e7. doi: 10.1016/j.chembiol.2022.03.001. Epub 2022 Mar 21.

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: LRH-1; agonist; coregulator; liver; nuclear receptor; phospholipid; ulcerative colitis; x-ray crystallography.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Colitis* / drug therapy
  • Ligands
  • Mice
  • Phospholipids* / therapeutic use
  • Receptors, Cytoplasmic and Nuclear* / agonists

Substances

  • Ligands
  • Nr5a2 protein, mouse
  • Phospholipids
  • Receptors, Cytoplasmic and Nuclear