title: Assay strategies for identification of therapeutic leads that target protein trafficking.
abstract: Receptors, enzymes, and ion channels are traditional targets of therapeutic development. A common strategy is to target these proteins with agents that either activate or suppress their activity with ligands or substrates that occupy orthosteric sites or have allosteric interactions. An alternative approach involves regulation of protein trafficking. In principle, this approach enables 'rescue' of misfolded and misrouted mutant proteins to restore function, 'shipwrecking' of undesirable proteins by targeting them for destruction, and regulation of levels of partially expressed wild type (WT) proteins at their functional sites of action. Here, we present drug discovery strategies that identify 'pharmacoperones', which are small molecules that serve as molecular templates and cause otherwise misfolded mutant proteins to fold and route correctly.
authors.affiliation: Department of Internal Medicine, Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Department of Cell Biology/Biochemistry, Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX, USA. Electronic address: pmichaelconn@gmail.com.
authors.forename: P Michael
authors.initials: PM
authors.lastname: Conn
authors.affiliation: Lead Identification Division, Translational Research Institute and Department of Molecular Therapeutics, Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Spicer
authors.affiliation: Lead Identification Division, Translational Research Institute and Department of Molecular Therapeutics, Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Louis
authors.initials: L
authors.lastname: Scampavia
authors.affiliation: Department of Internal Medicine, Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Department of Cell Biology/Biochemistry, Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
authors.forename: Jo Ann
authors.initials: JA
authors.lastname: Janovick
mesh_terms: D000818:Animals; D055808:Drug Discovery / Q000379:methods*; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D017510:Protein Folding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
chemical_list: D043562:Receptors, G-Protein-Coupled; D054852:Small Molecule Libraries
keywords: GPCR; mutant rescue; pharmacoperones; protein folding; protein mutants; protein trafficking