Open AccessOn the Design of Broad Based Screening Assays to Identify Potential Pharmacological Chaperones of Protein Misfolding Diseases
Author(s) -
Subhashchandra Naik,
Na Zhang,
Phillip Gao,
Mark T. Fisher
Publication year - 2013
Publication title -
current topics in medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.706
H-Index - 116
eISSN - 1873-4294
pISSN - 1568-0266
DOI - 10.2174/1568026611212220006
Subject(s) - groel , protein folding , computational biology , small molecule , chaperonin , surface plasmon resonance , drug discovery , protein aggregation , chaperone (clinical) , folding (dsp implementation) , chemistry , biology , bioinformatics , medicine , nanotechnology , biochemistry , materials science , engineering , escherichia coli , pathology , nanoparticle , electrical engineering , gene
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.