Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.01.278291v1?rss=1 Authors: 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. Abstract: As ligands for nuclear hormone receptors (NRs), phosphatidylcholines are powerful signaling molecules. Here, we demonstrate that mimicking phosphatidylcholine-NR interactions is a robust strategy for improving agonists of liver receptor homolog-1 (LRH-1), a promising therapeutic target for diabetes and colitis. Conventional LRH-1 modulators only occupy part of the binding pocket, leaving vacant a region important for phosphatidylcholine binding and allostery. Therefore, we constructed a set of hybrid molecules that incorporate elements of natural phosphatidylcholines into the scaffold of a synthetic LRH-1 agonist. The phosphatidylcholine-mimicking group increases LRH-1 binding affinity and transcriptional activity via formation of productive interactions with residues that coordinate the phosphatidylcholine headgroup. In organoid and in vivo models of colitis, the best new agonist upregulates LRH-1-controlled anti-inflammatory genes and significantly improves colonic histopathology and disease-related weight loss. This is the first evidence of in vivo efficacy for an LRH-1 modulator in colitis, a leap forward in agonist development. Copy rights belong to original authors. Visit the link for more info