Phospholipids serve as powerful signaling molecules, and have also been identified as ligands for Liver Receptor Homologue-1 (LRH-1). LRH-1 has been demonstrated as a viable nuclear receptor target for metabolic diseases, including type 2 diabetes and colitis, but synthetic ligands for this receptor are scarce due to the propensity of small molecules to unpredictably rotate in the large, lipophilic ligand binding pocket. Guided by new crystallographic data, we combined aspects of both synthetic small molecule ligands and naturally-occurring phosphatidylcholines into a single scaffold, effectively mimicking phosphatidylcholine interactions as a robust strategy for targeting LRH-1. Our compounds are shown to be a uniquely active class of LRH-1 modulators, and demonstrate <i>in vivo</i> activity against colitis.

Synthesis and mechanistic investigation of phospholipid-mimicking small molecules as synthetic modulators for liver receptor homologue-1

2019 Fall National Meeting

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