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

Cornelison, Jeffery L.; Cato, Michael L.; Johnson, Alyssa M.; D’Agostino, Emma H.; Melchers, Diana; Patel, Anamika; Mays, Suzanne G.; Ortlund, Eric A.; Jui, Nathan T.

doi:10.1016/j.bmcl.2020.127293

Cited by 18 publications

(32 citation statements)

References 30 publications

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“…FXR regulation of bile acid synthesis, transport and hepato-enteric circulation. Cyp7a1 is the rate limiting enzyme in BA synthesis, and it is transactivated by LXRα, HNF4α, and LHR-1 which in turn are stimulated by various ligands derived from lipid nutrients including cholesterol (for LXRα), fatty acyl-CoA (for HNF4α), dietary phospholipids for LRH-1 or liver receptor homologue-1 [18,19]. When BA becomes abundant in the liver, a negative feedback loop starts to function via FXR to maintain balance and to control the elimination of excess BA.…”

Section: Fxrmentioning

confidence: 99%

Farnesoid X Receptor as Target for Therapies to Treat Cholestasis-Induced Liver Injury

Petrescu

DeMorrow

2021

Cells

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Recent studies on liver disease burden worldwide estimated that cirrhosis is the 11th most common cause of death globally, and there is a great need for new therapies to limit the progression of liver injuries in the early stages. Cholestasis is caused by accumulation of hydrophobic bile acids (BA) in the liver due to dysfunctional BA efflux or bile flow into the gall bladder. Therefore, strategies to increase detoxification of hydrophobic BA and downregulate genes involved in BA production are largely investigated. Farnesoid X receptor (FXR) has a central role in BA homeostasis and recent publications revealed that changes in autophagy due to BA-induced reactive oxygen species and increased anti-oxidant response via nuclear factor E2-related factor 2 (NRF2), result in dysregulation of FXR signaling. Several mechanistic studies have identified new dysfunctions of the cholestatic liver at cellular and molecular level, opening new venues for developing more performant therapies.

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Section: Fxrmentioning

confidence: 99%

Farnesoid X Receptor as Target for Therapies to Treat Cholestasis-Induced Liver Injury

Petrescu

DeMorrow

2021

Cells

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“…20 Synthetic methods for RJW100 and analogs (compounds 1N-8N; 1X-8X; 9-23, used to generate Figure 2B) and compound 6Na have also been published previously. 25,36 Synthesis of diols (4OH-11OH) are described in detail in the supplemental materials.…”

Section: Methodsmentioning

confidence: 99%

“…We previously focused on strengthening deep pocket interactions made by RJW100, resulting in the discovery of the potent agonists 6N and 6Na (Figure 1c). 29,30 We used an alternative approach to design the PL-mimics, seeking to promote interactions near the mouth of the pocket.…”

Section: Structure-guided Design Of Pl-mimicsmentioning

confidence: 99%

“…We previously focused on strengthening deep pocket interactions made by RJW100, resulting in the discovery of the agonists 6N and 6Na (Figure S1). 24,25 For the PL-mimics, we used an alternative approach, seeking to promote interactions near the mouth of the pocket. Notably, the alkyl "tail" of RJW100 (position R 4 ) overlaps with the PL fatty acyl chains and follows a trajectory toward the pocket mouth (Figure 1a).…”

Section: Structure-guided Design Of Pl-mimicsmentioning

confidence: 99%

“…In addition to demarking differences between active and inactive compounds, the coregulator recruitment pattern of 9CA and 10CA also differs from that of 6N and 6Na, LRH-1 agonists that share the 6HP scaffold but are modified elsewhere on the molecule (Figure S1). 24,25 Unsupervised hierarchical clustering of the data shows a striking separation by ligand class: the most structurally similar ligands cluster together (Figure 4b). The close relationship between 9CA and 10CA in the clustering analysis appears to be due to common effects on coregulator dissociations.…”

Section: Effects On Lrh-1 Conformation and Coregulator Bindingmentioning

confidence: 99%

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A novel phospholipid mimetic targeting LRH-1 ameliorates colitis

Mays

D’Agostino

Flynn

et al. 2020

Preprint

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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.

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The nuclear receptor LRH‐1 discriminates between ligands using distinct allosteric signaling circuits

Mays,

Hercules,

Ortlund

et al. 2023

Protein Science

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Nuclear receptors (NRs) are transcription factors that regulate essential biological processes in response to cognate ligands. An important part of NR function involves ligand‐induced conformational changes that recruit coregulator proteins to the activation function surface (AFS), ~15 Å away from the ligand binding pocket. Ligands must communicate with the AFS to recruit appropriate coregulators and elicit different transcriptional outcomes, but this communication is poorly understood. These studies illuminate allosteric communication networks underlying activation of liver receptor homolog‐1 (LRH‐1), a NR that regulates development, metabolism, cancer progression and intestinal inflammation. Using >100 microseconds of all‐atom molecular dynamics simulations involving 74 LRH‐1 complexes, we identify distinct signaling circuits used by active and inactive ligands for AFS communication. Inactive ligands communicate via strong, coordinated motions along paths through the receptor to the AFS. Activating ligands disrupt the “inactive” circuit and induce connectivity with a second allosteric site. Ligand‐contacting residues in helix 7 help mediate the switch between circuits, suggesting new avenues for developing LRH‐1‐targeted therapeutics. We also elucidate aspects of coregulator signaling, showing that localized, destabilizing fluctuations are induced by inappropriate ligand‐coregulator pairings. These studies have uncovered novel features of LRH‐1 allostery, and the quantitative approach used to analyze many simulations provides a framework to study allosteric signaling in other receptors.This article is protected by copyright. All rights reserved.

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

Cited by 18 publications

References 30 publications

Farnesoid X Receptor as Target for Therapies to Treat Cholestasis-Induced Liver Injury

Farnesoid X Receptor as Target for Therapies to Treat Cholestasis-Induced Liver Injury

A novel phospholipid mimetic targeting LRH-1 ameliorates colitis

The nuclear receptor LRH‐1 discriminates between ligands using distinct allosteric signaling circuits

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