Biology subjects

Mays, S. G.

Publications and source records attributed to Mays, S. G..

4 recordsLinked to original sources

bioRxiv2026

An LRH-1 agonist reverses hepatic metabolic dysfunction in obesity

Liver receptor homolog-1 (LRH-1; NR5A2) is a nuclear receptor that controls metabolic gene programs important for liver health. Here, we address two challenges with dissecting ligand-driven LRH-1 metabolism in vivo. First, we generate ME610, a potent LRH-1 agonist with favorable pharmacokinetic properties. Second, we engineer Nr5a2humLBD mice, edited to recapitulate the ligand response of the human receptor. ME610 dose-dependently induces LRH-1 target genes and reduces triglycerides in livers of Nr5a2humLBD mice. In a mouse model of diet-induced obesity (DIO), ME610 dramatically improves insulin sensitivity and reduces liver fat. Multi-omics integration of transcriptomics, lipidomics, and metabolomics data demonstrates a coordinated reversal of DIO-induced hepatic metabolic stress via changes in lipid, amino acid, and energy metabolism, with peroxisomal lipid metabolism emerging as a central process correlated to efficacy. These studies uncover new pathways through which LRH-1 regulates metabolism and demonstrate the therapeutic potential of synthetic LRH-1 agonists in obesity-associated metabolic diseases.

physiology↗

bioRxiv2020

Tapping into a phospholipid-LRH-1 axis yields a powerful anti-inflammatory agent with in vivo activity against colitis

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.

biochemistry↗

bioRxiv2020

Development of a new class of liver receptor homolog-1 (LRH-1) agonists by photoredox conjugate addition

LRH-1 is a nuclear receptor that regulates lipid metabolism and homeostasis, making it an attractive target for the treatment of diabetes and non-alcoholic fatty liver disease. Building on recent structural information about ligand binding from our labs, we have designed a series of new LRH-1 agonists that further engage LRH-1 through added polar interactions. While the current synthetic approach to this scaffold has, in large part, allowed for decoration of the agonist core, significant variation of the bridgehead substituent is mechanistically precluded. We have developed a new synthetic approach to overcome this limitation, identified that bridgehead substitution is necessary for LRH-1 activation, and described an alternative class of bridgehead substituents for effective LRH-1 agonist development. We determined the crystal structure of LRH-1 bound to a bridgehead-modified compound, revealing a promising opportunity to target novel regions of the ligand-binding pocket to alter LRH-1 target gene expression.

biochemistry↗

bioRxiv2019

Development of the first low nanomolar Liver Receptor Homolog-1 agonist through structure-guided design

As a key regulator of metabolism and inflammation, the orphan nuclear hormone receptor, Liver Receptor Homolog-1 (LRH-1), has potential as a therapeutic target for diabetes, nonalcoholic fatty liver disease, and inflammatory bowel diseases. Discovery of LRH-1 modulators has been difficult, in part due to the tendency for synthetic compounds to bind unpredictably within the lipophilic binding pocket. Using a structure-guided approach, we exploited a newly-discovered polar interaction to lock agonists in a consistent orientation. This enabled the discovery of the first low nanomolar LRH-1 agonist, one hundred times more potent than the best previous modulator. We elucidate a novel mechanism of action that relies upon specific polar interactions deep in the LRH-1 binding pocket. In an organoid model of inflammatory bowel disease, the new agonist increases expression of LRH-1-conrolled steroidogenic genes and promotes anti-inflammatory gene expression changes. These studies constitute major progress in developing LRH-1 modulators with potential clinical utility.

pharmacology and toxicology↗