A Phospholipid Mimetic Targeting LRH-1 Ameliorates Colitis

Authors

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

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

Published Open-Access

yes

Keywords

Animals, Colitis, Ligands, Mice, Phospholipids, Receptors, Cytoplasmic and Nuclear, Phospholipid, LRH-1, nuclear receptor, agonist, ulcerative colitis

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.