Tapping into a phospholipid-LRH-1 axis yields a powerful anti-inflammatory agent with in vivo activity against colitis
Mays, S. G.; D'Agostino, E. H.; Flynn, A. R.; Huang, X.; Wang, G.; Liu, X.; Millings, E. J.; Okafor, C. D.; Patel, A.; Cato, M. L.; Cornelison, J. L.; Melchers, D.; Houtman, R.; Moore, D. D.; Calvert, J. W.; Jui, N. T.; Ortlund, E. A.
Show abstract
Phospholipids are ligands for nuclear hormone receptors (NRs) and regulate transcriptional programs relevant to normal physiology and disease. Here, we demonstrate that mimicking phospholipid-NR interactions greatly improves agonists of liver receptor homolog-1 (LRH-1), a promising therapeutic target for diabetes and colitis. Conventional LRH-1 modulators partially occupy the binding pocket, leaving vacant a region important for phospholipid binding and allostery. Therefore, we constructed a set of hybrid molecules with elements of natural phospholipids appended to a synthetic LRH-1 agonist. The phospholipid-mimicking group improves binding affinity, increases LRH-1 transcriptional activity, promotes coregulator recruitment, and interacts with the targeted LRH-1 residues in crystal structures. The best new agonist markedly improves colonic histopathology and disease-related weight loss in a humanized LRH-1 murine T-cell transfer model of colitis. This is the first evidence of in vivo efficacy for an LRH-1 modulator in colitis, a leap forward in agonist development.
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