New screening strategy and analysis for identification of allosteric modulators for glucagon-like peptide-1 receptor using GLP-1 (9-36) amide

Analytical Biochemistry
Atsushi NakaneHidetaka Nagata

Abstract

The glucagon-like peptide-1 receptor (GLP-1R) is an important physiologic regulator of insulin secretion and a major therapeutic target for diabetes mellitus. GLP-1 (7-36) amide (active form of GLP-1) is truncated to GLP-1 (9-36) amide, which has been described as a weak agonist of GLP-1R and the major form of GLP-1 in the circulation. New classes of positive allosteric modulators (PAMs) for GLP-1R may offer improved therapeutic profiles. To identify these new classes, we developed novel and robust primary and secondary high-throughput screening (HTS) systems in which PAMs were identified to enhance the GLP-1R signaling induced by GLP-1 (9-36) amide. Screening enabled identification of two compounds, HIT-465 and HIT-736, which possessed new patterns of modulation of GLP-1R. We investigated the ability of these compounds to modify GLP-1R signaling enhanced GLP-1 (9-36) amide- and/or GLP-1 (7-36) amide-mediated cyclic adenosine monophosphate (cAMP) accumulation. These compounds also had unique profiles with regard to allosteric modulation of multiple downstream signaling (PathHunter β-arrestin signaling, PathHunter internalization signaling, microscopy-based internalization assay). We found allosteric modulation patterns to be ob...Continue Reading

References

Aug 22, 1997·The Journal of Biological Chemistry·C Montrose-RafizadehJ Eng
Jan 11, 2007·Proceedings of the National Academy of Sciences of the United States of America·Lotte Bjerre KnudsenJesper Lau
Feb 20, 2007·Pharmacology & Therapeutics·Máire E Doyle, Josephine M Egan
May 15, 2007·Gastroenterology·Laurie L Baggio, Daniel J Drucker
Oct 12, 2007·Physiological Reviews·Jens Juul Holst
Feb 24, 2011·Biochemistry·Michael R WoodCraig W Lindsley
Jun 6, 2012·Experimental Diabetes Research·Francis S Willard, Kyle W Sloop
Oct 24, 2012·Proceedings of the National Academy of Sciences of the United States of America·Kaleeckal G HarikumarPatrick M Sexton
Jan 30, 2013·Biochemical Society Transactions·Cassandra KoolePatrick M Sexton
Feb 15, 2014·Journal of Biomolecular Screening·Lindsey C MorrisKevin D Niswender
May 23, 2014·Frontiers in Endocrinology·Etienne KhouryStéphane A Laporte

❮ Previous
Next ❯

Related Concepts

Related Feeds

Calcium & Bioenergetics

Bioenergetic processes, including cellular respiration and photosynthesis, concern the transformation of energy by cells. Here is the latest research on the role of calcium in bioenergetics.

Advanced Imaging of Cellular Signaling

Cell signaling is a vital mechanism for communication within cells and outside with the environment. Several different signaling pathways have been found and advanced imaging techniques are being developed to visualize the molecules involved in these signaling pathways. Find the latest research in advanced imaging of cellular signaling here.

Cardiovascular Biology of GLP-1

Glucagon-like peptide 1 (GLP-1) plays a role in glucose metabolism, energy homeostasis, and inflammation suppression. GLP-1 receptor signaling has been shown to impact cardiovascular function. This feed focuses on the role of GLP-1 and GLP-1 receptor agonists on cardiovascular biology.