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A Novel High-Throughput Screening Assay for Putative Antidiabetic Agents through PPAR Interactions

Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, Texas

Lindsay R. Syler

Department of Pathobiology, Texas A&M University, TVMC, College Station, Texas

Lindy N. Hall

Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, Texas

Guan Zhu

Department of Pathobiology, Texas A&M University, TVMC, College Station, Texas

Friedhelm Schroeder

Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, Texas

Ann B. Kier

Department of Pathobiology, Texas A&M University, TVMC, College Station, Texas, akier{at}cvm.tamu.edu

As natural peroxisome proliferator-activated receptor- (PPAR) ligands, high levels of fatty acids and glucose could lead to hyperactivation of PPAR, like that seen in diabetes. Important diabetes research goals are to uncover new metabolic or signaling pathways involved in hyperglycemic cellular injury and to develop therapeutics for preventing or reversing this injury. Consequently, 1040 putative antidiabetic agents were screened for their ability to 1) affect PPAR lipid binding, 2) directly bind PPAR, and 3) alter PPAR transactivation in the presence of high glucose. A high-throughput fluorescent binding assay was developed to examine each compound's ability to restore fatty acyl-CoA binding to PPAR in the presence of high glucose concentrations. Approximately 1% of the compounds restored acyl-CoA binding by 60% or more. These compounds directly interacted with PPAR with high affinity (nM K_ds), validating the primary screen. Furthermore, these compounds altered PPAR transactivation, and 1 strongly reversed the hyperactivation of PPAR found in the presence of clofibrate and high glucose levels. (Journal of Biomolecular Screening 2008:855-861)

Key Words: nuclear transcription factors • peroxisome proliferator-activated receptors • fluorescent binding assays • glucose

This version was published on October 1, 2008

Journal of Biomolecular Screening, Vol. 13, No. 9, 855-861 (2008)
DOI: 10.1177/1087057108323127


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