title: On the design of broad based screening assays to identify potential pharmacological chaperones of protein misfolding diseases.
abstract: Correcting aberrant folds that develop during protein folding disease states is now an active research endeavor that is attracting increasing attention from both academic and industrial circles. One particular approach focuses on developing or identifying small molecule correctors or pharmacological chaperones that specifically stabilize the native fold. Unfortunately, the limited screening platforms available to rapidly identify or validate potential drug candidates are usually inadequate or slow because the folding disease proteins in question are often transiently folded and/or aggregation-prone, complicating and/or interfering with the assay outcomes. In this review, we outline and discuss the numerous platform options currently being employed to identify small molecule therapeutics for folding diseases. Finally, we describe a new stability screening approach that is broad based and is easily applicable toward a very large number of both common and rare protein folding diseases. The label free screening method described herein couples the promiscuity of the GroEL binding to transient aggregation-prone hydrophobic folds with surface plasmon resonance enabling one to rapidly identify potential small molecule pharmacological chaperones.
authors: University of Kansas Medical Center, Department of Biochemistry, Kansas City, KS, USA.
authors: Subhashchandra
authors: S
authors: Naik
authors: Na
authors: N
authors: Zhang
authors: Phillip
authors: P
authors: Gao
authors: Mark T
authors: MT
authors: Fisher
mesh_terms: D018834:Chaperonin 60 / Q000737:chemistry; D003198:Computer Simulation; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D018832:Molecular Chaperones / Q000494:pharmacology*; D058990:Molecular Targeted Therapy / Q000379:methods*; D020125:Mutation, Missense; D017510:Protein Folding; D057165:Proteostasis Deficiencies / Q000188:drug therapy* / Q000628:therapy; D020349:Surface Plasmon Resonance
chemical_list: C505032:CFTR protein, human; D018834:Chaperonin 60; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator