Abstract
Nuclear hormone receptors are ligand-activated transcription factors that regulate gene expression and play a critical role in endocrine signaling. Orphan nuclear receptors belong to this gene super-family but their target genes and physiological function have not been completely elucidated. In recent years, the identification of natural ligands for these orphan receptors, their expression pattern in different tissues and studies with knock-out animals has delineated distinct regulatory functions for these proteins. The orphans belonging to the PPAR, LXR and FXR family function as lipid and bile-acid sensors while PXR and CAR function as xenobiotic sensors. This review will describe the discovery of natural and synthetic ligands for a number of these orphan receptors (excluding the PPARs) and the identification and characterization of novel signaling pathways and new hormone response systems linked to these targets. Small-molecule modulators of LXR and FXR control key genes involved in cholesterol and lipid metabolism. PXR is a highly promiscuous xenosensor that responds to xenobiotic ligands (antibiotics, statins, glucocorticoids) and induces the Cyp3A gene, thereby playing a role in hepatoprotection and bile acid metabolism. A related receptor from the gene subfamily, CAR, displays high ligand selectivity and modulation of its activity in humans may significantly alter metabolism of drugs and other xenobiotics. The role of the ER relatives, the ERRs will become more apparent as ligands are identified and linked to target genes and physiological function. These targets offer multiple opportunities for therapeutic intervention with small-molecule drugs, in diseases related to neuronal function, inflammation, lipid homeostasis, metabolic function and cancer.
Keywords: orphan nuclear, receptor modulators, lipid homeostasis, cyp3a gene, xenobiotic ligands, xenobiotic sensors, bile-acid sensors, fxr family, orphan receptors, nuclear hormone receptors
Current Topics in Medicinal Chemistry
Title: Orphan Nuclear Receptor Modulators
Volume: 3 Issue: 14
Author(s): Raju Mohan and Richard A. Heyman
Affiliation:
Keywords: orphan nuclear, receptor modulators, lipid homeostasis, cyp3a gene, xenobiotic ligands, xenobiotic sensors, bile-acid sensors, fxr family, orphan receptors, nuclear hormone receptors
Abstract: Nuclear hormone receptors are ligand-activated transcription factors that regulate gene expression and play a critical role in endocrine signaling. Orphan nuclear receptors belong to this gene super-family but their target genes and physiological function have not been completely elucidated. In recent years, the identification of natural ligands for these orphan receptors, their expression pattern in different tissues and studies with knock-out animals has delineated distinct regulatory functions for these proteins. The orphans belonging to the PPAR, LXR and FXR family function as lipid and bile-acid sensors while PXR and CAR function as xenobiotic sensors. This review will describe the discovery of natural and synthetic ligands for a number of these orphan receptors (excluding the PPARs) and the identification and characterization of novel signaling pathways and new hormone response systems linked to these targets. Small-molecule modulators of LXR and FXR control key genes involved in cholesterol and lipid metabolism. PXR is a highly promiscuous xenosensor that responds to xenobiotic ligands (antibiotics, statins, glucocorticoids) and induces the Cyp3A gene, thereby playing a role in hepatoprotection and bile acid metabolism. A related receptor from the gene subfamily, CAR, displays high ligand selectivity and modulation of its activity in humans may significantly alter metabolism of drugs and other xenobiotics. The role of the ER relatives, the ERRs will become more apparent as ligands are identified and linked to target genes and physiological function. These targets offer multiple opportunities for therapeutic intervention with small-molecule drugs, in diseases related to neuronal function, inflammation, lipid homeostasis, metabolic function and cancer.
Export Options
About this article
Cite this article as:
Mohan Raju and Heyman A. Richard, Orphan Nuclear Receptor Modulators, Current Topics in Medicinal Chemistry 2003; 3 (14) . https://dx.doi.org/10.2174/1568026033451709
DOI https://dx.doi.org/10.2174/1568026033451709 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Novel Drugs for Inflammatory Lung Diseases
Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents Therapeutic Neovascularization by the Implantation of Autologous Mononuclear Cells in Patients with Connective Tissue Diseases
Current Pharmaceutical Design Overview on the Tricks of HIV Tat to Hit the Blood Brain Barrier
Current HIV Research Indoleamine 2,3-dioxygenase (IDO): Biology and Target in Cancer Immunotherapies
Current Cancer Drug Targets Peptide-Mediated Cellular Delivery of Oligonucleotide-Based Therapeutics In Vitro: Quantitative Evaluation of Overall Efficacy Employing Easy to Handle Reporter Systems
Current Pharmaceutical Design Polysulfated/Sulfonated Compounds for the Development of Drugs at the Crossroad of Viral Infection and Oncogenesis
Current Pharmaceutical Design Effects of Opiates and HIV Proteins on Neurons: The Role of Ferritin Heavy Chain and a Potential for Synergism
Current HIV Research Helicobacter pylori Current Chemotherapy and New Targets for Drug Design
Current Pharmaceutical Design Nutraceuticals and "Repurposed" Drugs of Phytochemical Origin in Prevention and Interception of Chronic Degenerative Diseases and Cancer
Current Medicinal Chemistry Immunomodulatory Drugs: IMiDs in Acute Myeloid Leukemia (AML)
Current Drug Targets Multitarget Network Strategies to Influence Memory and Forgetting: The Ras/Mapk Pathway as a Novel Option
Mini-Reviews in Medicinal Chemistry Myalgic Encephalomyelitis: Symptoms and Biomarkers
Current Neuropharmacology Vitamin D Insufficiency and Diabetes Risks
Current Drug Targets Down-Regulation of Angiogenic Inhibitors: A Potential Pathogenic Mechanism for Diabetic Complications
Current Diabetes Reviews Polymeric Nanoparticles for Ophthalmic Drug Delivery: An Update on Research and Patenting Activity
Recent Patents on Nanomedicine Leukotrienes, Antileukotrienes and Asthma
Mini-Reviews in Medicinal Chemistry Oncolytic Viruses for Induction of Anti-Tumor Immunity
Current Pharmaceutical Biotechnology Epigenetic MicroRNA Regulation of Multiple Chromatin Functions: A Perspective in Cancer
Epigenetic Diagnosis & Therapy (Discontinued) Vitamin D and Cardiovascular Disease
Current Vascular Pharmacology Across the Universe of K-Ras Mutations in Non-Small-Cell-Lung Cancer
Current Pharmaceutical Design