Chapter 25. Nuclear Orphan Receptors: Scientific Progress and Therapeutic Opportunities

Abstract

Publisher Summary In recent times, nuclear orphan receptor research has had a major impact on the fields of molecular and cell biology, endocrine physiology, and pharmacology. Nuclear receptors are a superfamily of ligand-gated transcription factors that are regulated, in many cases by the binding of small lipid-soluble ligands. This superfamily of proteins includes the known receptors for steroid and thyroid hormones, vitamin A, and vitamin D as well as a large number of newly discovered orphan receptors for which ligand activators is initially unknown. As many of these orphan receptors are also associated with metabolic and inherited disorders, they are logical targets for the development of improved medicines to treat a variety of endocrine and metabolic diseases. The objective of this chapter is to highlight the recent biological discoveries in this field, with particular emphasis on the examples of novel pharmacologically active compounds that regulate these transcription factors. Almost 60 nuclear orphan receptors have been discovered so far and almost half of these are present in vertebrates. Delineation of the physiologic function of these receptors has proven to be a daunting challenge, but pharmacologic exploitation of several nuclear orphan receptors has revealed novel strategies for drug discovery. Most nuclear orphan receptors contain the same functional domains as the classical nuclear receptors. Steroid receptors bind to DNA exclusively, as homodimers on response elements arranged as palindromic repeats of two consensus hexanucleotide half-sites. Virtually all these nuclear orphan receptors have been identified in human tissues, underscoring their physiologic significance and possible therapeutic importance. Many of these receptors exist as multiple subtypes that represent the product of discrete individual genes. These receptor subtypes frequently manifest distinct but overlapping patterns of expression, and because the family of target genes they regulate are generally different, these receptor subtypes represent logical avenues for the design of medicines with selective therapeutic effects.