oa Editorial [Hot Topic :Current Advances In Therapeutic Applications of Nuclear Receptors (Guest Editor: Stefano Fiorucci)]

This issue of Current Topic of Medicinal Chemistry highlight several aspects of the medicinal chemistry of nuclear receptors and their relevance in drug discovery by collecting comprehensive reviews from outstanding investigators involved in the field and examines the biology of specific subfamilies of these ligand-activated regulatory factors that might have relevance in the therapy of a wide variety of human alignments. The nuclear receptor family contains a large group of transcription factors, with 49 members presently identified in the human genome. The activity of most nuclear receptors is mediated by the binding of small lipophilic ligands such as steroid and thyroid hormones, bile acids, fatty acids, and retinoids. Nuclear receptors are active as either homo- or hetero-dimers and regulate transcription by binding to response elements in the regulatory regions of target genes. Over the past two decades significant advances have been made in the understanding of the regulation of gene expression by these regulatory elements. In many cases, the characterization of the receptor has preceded the study of the function and the identification of a ligand. In the past few years, the ligands for these orphan receptors have been identified and in many cases have turned out to be products of normal metabolism. These receptors regulate a diverse collection of genes that control cell differentiation and growth, lipid and glucose metabolism, and immune functions. Examples of drugs acting on nuclear receptors are glitazones, targeting PPARγ, estrogens for hormone replacement therapy, antiestrogens for treatment of cancer, and various steroids for treatment of inflammatory disorders. Most of the drugs on the market that act through the modulation of nuclear receptor activity were developed with an incomplete understanding of the receptor that they target. In consequence, they have side effects due to lack of receptor specificity or tissue selectivity. Increased understanding of the structure and function of nuclear receptors and their role in health and disease makes it possible to improve existing therapies and to treat new disorders with novel, more precise drugs that target nuclear receptors. The article by Michael Pawlak, Philippe Lefebvre and Bart Staels from the INSERM UMR1011, Institut Pasteur de Lille, is focused on the “General molecular biology and architecture of nuclear receptors”. The article examines the general biology of nuclear receptors. Nuclear hormone receptors function as ligand-activated transcription factors, and thus provide a direct link between signaling molecules that control these processes and transcriptional responses. A large number of nuclear receptors have been identified through sequence similarity to known receptors, but have no identified natural ligand, and are referred to as “nuclear orphan”. The article describes the general molecular architecture of this family of ligand activated regulatory factors and how they impact on chromatin remodeling. The article by Albane le Maire, Susana Alvarez, Pattabhiraman Shankaranarayanan, Angel R de Lera, William Bourguet and Hinrich Gronemeyer from Starsbourg, entitled: “Receptors and therapeutic applications of RAR/RXR modulators” examines the biology of retinoic acid receptors (RARs). RXRs are ligand-controlled transcription factors that function as heterodimers with retinoid X receptors (RXRs) to regulate cell growth, differentiation, survival and death. Due to their regulatory potential, these nuclear receptors are major drug targets for a variety of pathologies, including cancer and metabolic diseases. A large amount of RAR- and RXR-selective ligands, ranging from (partial) agonists to antagonists and inverse agonists, have been designed and the corresponding structural and functional analyses have provided deep insight into the molecular basis of ligand action. The third review by Carsten Carlberg and Ferdinand Molnar from the University of Eastern Finland, Kuopio, Finland, entitled: “Current status of Vitamin D signaling and therapeutic potentials” is focused on the Vitamin D (Vit. D). Vitamin D and in particular its biologically most active metabolite, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), are central endocrine molecules that influence many aspects of human physiology, which are not only the well-known calcium and phosphorus uptake and transport controlling bone formation, but also the control of immune functions and of cellular growth and differentiation. The review is focused on the latest insight into vitamin D signaling in context with the most prominent 1α,25(OH)2D3 analogues. The fourth review by Maria P. Menendez-Gutierre, Tamas Roszer, Mercedes Ricote from Madrid, entitled: “Biology and therapeutic applications of peroxisome proliferator-activated receptors” is focused on the biology of potential therapeutic applications of peroxisome proliferator-activated receptors (PPARs). Similar to RXRs and VDR, PPARα, β, γ/δ are ligand dependent transcription factors. The three mammalian PPARs are key regulators of fatty acid and lipoprotein metabolism, glucose homeostasis, cellular proliferation/differentiation and the immune response. PPARs are therefore important targets in the treatment of metabolic disorders such as insulin resistance and type 2 diabetes mellitus, and are also of interest in relation to chronic inflammatory diseases such as atherosclerosis, arthritis, chronic pulmonary inflammation, pancreatitis, inflammatory bowel disease, and psoriasis. The review gives an overview of PPAR functions and discusses the current and potential medical implications of PPAR ligands in various pathologies, ranging from metabolic disorders to cardiovascular disease, chronic inflammation, neurodegenerative disorders and cancer. The review by Dr. Andreea Ciudin, Cristina Hernandez, Rafael Simo mfrom Barcelona, entitled “Update on Cardiovascular safety of PPARgamma agonists and relevance to medicinal chemistry and clinical pharmacology” has examined the “dark side” of the highly successful class of drugs, the glitazones, that specifically targets the PPARγ and have been widely used in the treatment of diabetes. Based on available evidence, glitazones have shown similar effects on glycemic control, as well as a range of similar adverse effects. The article outlines the need for development of novel class of PPARγ ligands or, perhaps better, for development of PPARβ/δ. An approach to select the desirable therapeutic effects of the full PPARγ agonists, and eliminate the unwanted side effects is the development of the selective PPAR modulators (known as SPPARMs). Little differences between the full PPARγ agonists versus SPPARMs determine changes in the conformation of receptor which can lead to changes in cofactor recruitment and transcriptional regulation. The sixth review by Stefano Fiorucci, Angela Zampella and Eleonora Distrutti, from Perugia and Naples, entitled: “Development of FXR, PXR and CAR agonists and antagonists for treatment of liver disorders” is focused on a family of nuclear receptors that specifically senses bile acids. Bile acids are the end-product of cholesterol breakdown and their concentration in the entero-hepatic tissues is sensed by several nuclear receptors, more specifically by the farnesoid-x-receptor (FXR), the constitute-androstane-receptor (CAR) and the pregnane-x-receptor (PXR) and also by VDR. FXR agonists are currently under clinical investigations but their use associates with potential side-effects. Structure-activity relationship studies have shown that available FXR antagonists are poorly specific for FXR, however the recent discovery of selective antagonists from marine sponges has ground the identification/development of specific FXR antagonists that are currently used in pre-clinical models of liver injury. The review is focused on the latest update in the identification of FXR and PXR agonists and antagonists and exploitation of their use in preclinical models of human pathologies. The article by Barbara Renga, Andrea Mencarelli, Sabrina Cipriani and Eleonora Distrutti all from Perugia, examines a novel field of interest in area of “Molecular determinants of Gastrointestinal and liver cancers: Role of Bile acid activated Nuclear Receptors”. The article examines the role of bile acids regulated nuclear receptors in regulating critical steps cell growth and differentiation and how bile acid-activated receptors could be involved in development of gastrointestinal cancers. The final review article of this issue by Maria Valeria d'Auria, Valentina Sepe and Angela Zampella, all from Naples, entitled: “Natural ligands for nuclear receptors: biology and potential therapeutic applications” is focused on the discovery of novel natural compounds, from marine and vegetal realms, targeting nuclear receptors and therefore useful for the treatment of a variety of diseases, such as cancer, diabetes, dyslipidemia, fatty liver disease, drug hepatotoxicity and cholestasis. As a guest Editor I wish to warmly thank all the authors who contributed articles in this Special Issue. I'm also grateful to each and every scientist who reviewed manuscripts for this Special Issue.