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J Biomol Screen

Title:		"Cell-permeable, small-molecule activators of the insulin-degrading enzyme"
Author(s):		Kukday SS; Manandhar SP; Ludley MC; Burriss ME; Alper BJ; Schmidt WK;
Address:		"The University of Georgia, Athens, GA, USA"
Journal Title:		J Biomol Screen
Year:		2012
Volume:		20120626
Issue:		10
Page Number:		1348 - 1361
DOI:		10.1177/1087057112451921
ISSN/ISBN:		1552-454X (Electronic) 1087-0571 (Print) 1087-0571 (Linking)
Abstract:		"The insulin-degrading enzyme (IDE) cleaves numerous small peptides, including biologically active hormones and disease-related peptides. The propensity of IDE to degrade neurotoxic Abeta peptides marks IDE as a potential therapeutic target for Alzheimer disease. Using a synthetic reporter based on the yeast a-factor mating pheromone precursor, which is cleaved by multiple IDE orthologs, we identified seven small molecules that stimulate rat IDE activity in vitro. Half-maximal activation of IDE by the compounds is observed in vitro in the range of 43 to 198 microM. All compounds decrease the K(m) of IDE. Four compounds activate IDE in the presence of the competing substrate insulin, which disproportionately inhibits IDE activity. Two compounds stimulate rat IDE activity in a cell-based assay, indicating that they are cell permeable. The compounds demonstrate specificity for rat IDE since they do not enhance the activities of IDE orthologs, including human IDE, and they appear specific for a-factor-based reporters since they do not enhance rat IDE-mediated cleavage of Abeta-based reporters. Our results suggest that IDE activators function in the context of specific enzyme-substrate pairs, indicating that the choice of substrate must be considered in addition to target validation in IDE activator screens"
Keywords:		"Animals *Cell Membrane Permeability Dose-Response Relationship, Drug Enzyme Activation/drug effects Enzyme Activators/pharmacokinetics/*pharmacology High-Throughput Screening Assays Humans Insulysin/*metabolism Kinetics Mating Factor Peptides/chemistry/me;"
Notes:		"MedlineKukday, Sayali S Manandhar, Surya P Ludley, Marissa C Burriss, Mary E Alper, Benjamin J Schmidt, Walter K eng R01 GM067092/GM/NIGMS NIH HHS/ 5R01GM067092/GM/NIGMS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2012/06/29 J Biomol Screen. 2012 Dec; 17(10):1348-61. doi: 10.1177/1087057112451921. Epub 2012 Jun 26"