Many human diseases result from mutations in specific genes. Once translated, the resulting aberrant proteins are often functionally competent and produced at normal levels. However, because of the mutations, the proteins are recognized as less stable by the quality control system of the endoplasmic reticulum (ER) and, as such, are not processed and trafficked correctly, ultimately leading to cellular dysfunction and disease. Small molecule pharmacological chaper-ones are a promising new therapeutic approach to treat these genetic disorders. Pharmacological chaperones selectively bind to the mutant proteins and stabilize a near-native conformation. This stabilization promotes normal trafficking of the mutant protein and allows passage through the ER quality control system, ultimately increasing protein levels and activity in relevant cellular locations and reducing ER accumulation, aggregation, and associated cell stress. Partial or complete restoration of normal function by pharmacological chaperones has been shown for numerous types of mutant proteins, including enzymes, secreted proteins, transcription factors, ion channels, and,

GPCR Molecular Pharmacology and Drug Targeting: Shifting Paradigms and New Directions,

Edited by Annette Gilchrist

Copyright © 2010 John Wiley & Sons, Inc.

importantly, G protein-coupled receptors (GPCRs). This review highlights human diseases that are known to result from genetic mutations that lead to less stable or misfolded intracellularly retained GPCRs, and hence have the potential for pharmacological chaperone therapy. Particular emphasis is given to those diseases that have established proof of concept for the beneficial effects of pharmacological chaperones on the underlying mutant GPCRs, as demonstrated in cells, animals, and/or humans, including X-linked nephrogenic diabetes insipidus, retinitis pigmentosa, and idiopathic hypogonadotropic hypogonadism. In addition, considerations for the successful use and development of novel pharmacological chaperone therapies will be discussed.

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