Investigation of an Improved Phospholipid-Mimicking Agonist of LRH-1 Open Access

Abraham, Sarah (Spring 2023)

Permanent URL: https://etd.library.emory.edu/concern/etds/7p88ch84k?locale=de%2F1000
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Abstract

Liver receptor homolog-1 (LRH-1; NR5A2) is a nuclear receptor that regulates glucose and bile acid homeostasis in the liver, intestine, and pancreas. We have recently reported small molecules that mimic phospholipid residue contacts at the binding pocket mouth through carboxylic acid tails. Here, we report a similar series of small molecules with different polar moieties that aim to make similar contacts. Using a tetrazole instead of the carboxylic acid improves potency, target gene expression, and binding at the mouth of the pocket. Combing a previous small molecule with the tetrazole design improves compound potency, binding, and thermal stability. The resulting small molecule is specific for NR5A receptors providing a useful tool for exploring LRH-1 biology and targeting the receptor in pathophysiological contexts.

Table of Contents

Introduction………………………………………………………………..1

Results………………………………………………………………….4

Discussion…………………………………………………………..12

Methods…………………………………………………………..15

References…………………………………………………………..24

Supplemental Information…………………………………………………………..28

 

 

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