A Duplexed High-Throughput Screen to Identify Allosteric Modulators of the Glucagon-Like Peptide 1 and Glucagon Receptors.

Morris LC, Days EL, Turney M, Mi D, Lindsley CW, Weaver CD, Niswender KD
J Biomol Screen. 2014 19 (6): 847-58

PMID: 24525870 · PMCID: PMC4306651 · DOI:10.1177/1087057114520971

Injectable, degradation-resistant peptide agonists for the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R), such as exenatide and liraglutide, activate the GLP-1R via a complex orthosteric-binding site and are effective therapeutics for glycemic control in type 2 diabetes. Orally bioavailable orthosteric small-molecule agonists are unlikely to be developed, whereas positive allosteric modulators (PAMs) may offer an improved therapeutic profile. We hypothesize that allosteric modulators of the GLP-1R would increase the potency and efficacy of native GLP-1 in a spatial and temporally preserved manner and/or may improve efficacy or side effects of injectable analogs. We report the design, optimization, and initial results of a duplexed high-throughput screen in which cell lines overexpressing either the GLP-1R or the glucagon receptor were coplated, loaded with a calcium-sensitive dye, and probed in a three-phase assay to identify agonists, antagonists, and potentiators of GLP-1, and potentiators of glucagon. 175,000 compounds were initially screened, and progression through secondary assays yielded 98 compounds with a variety of activities at the GLP-1R. Here, we describe five compounds possessing different patterns of modulation of the GLP-1R. These data uncover PAMs that may offer a drug-development pathway to enhancing in vivo efficacy of both endogenous GLP-1 and peptide analogs.

© 2014 Society for Laboratory Automation and Screening.

MeSH Terms (23)

Allosteric Regulation Allosteric Site Animals Binding Sites Calcium Cell Line Cell Line, Tumor CHO Cells Cricetinae Cricetulus Cyclic AMP Disease Progression Exenatide Glucagon-Like Peptide 1 Glucose High-Throughput Screening Assays Humans Liraglutide Peptides Receptors, Glucagon Recombinant Proteins Signal Transduction Venoms

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