title: Pharmacoperones as a New Therapeutic Approach: In Vitro Identification and In vivo Validation of Bioactive Molecules.
abstract: In many conformational diseases caused by protein mutations, the intracellular traffic of the misfolded protein is compromised, leading to reduced or abolished function of the affected protein. Pharmacoperones (from "pharmacological chaperones") are compounds that enter cells and serve as a molecular scaffold to aid misfolded mutant proteins to fold properly and adopt a stable, low-energy native conformation compatible with proper intracellular trafficking. The use of pharmacoperones represents the most promising therapeutic approach to treat misfolding disorders. This class of drugs has succeeded, in vitro and in vivo, in rescuing function of mutant, misfolded proteins, including enzymes, membrane receptors and ion channels. Here we describe the strategies to rescue function of misfolded G protein-coupled receptors, mainly of the gonadotropin-releasing hormone receptor, which has served as a valuable model for the development of pharmacoperone drugs and to better understand how this class of particular compounds is sensed by the target protein to correct routing, expression and function.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ulloa-Aguirre
authors.affiliation: Departments of Internal Medicine and Cell Biology/Biochemistry, Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, Texas, TX 79430-6252, USA. michael.conn@ttuhsc.edu.
authors.forename: P Michael
authors.initials: PM
authors.lastname: Conn
mesh_terms: D000818:Animals; D015195:Drug Design; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057165:Proteostasis Deficiencies / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D018832:Molecular Chaperones; D050505:Mutant Proteins; D011506:Proteins