Title:On the Design of Broad Based Screening Assays to Identify Potential Pharmacological Chaperones of Protein Misfolding Diseases
VOLUME: 12 ISSUE: 22
Author(s):Subhashchandra Naik, Na Zhang, Phillip Gao and Mark T. Fisher
Affiliation:University of Kansas Medical Center, Department of Biochemistry, Kansas City KS, USA.
Keywords:Protein misfolding, missense mutations, pharmacological chaperones, GroEL chaperonin, Surface Plasmon Resonance
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 aggregationprone,
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.
