Glucagon-like peptide-1 receptor (GLP-1R), a member of family B G protein-coupled receptors (GPCRs), is a highly attractive therapeutic target for type 2 diabetes. It has been shown clinically that the activation of GLP- 1R has many anti-diabetic effects, including potentiating insulin biosynthesis, increasing glucose-dependent insulin secretion, inhibiting pancreatic -cell apoptosis and promoting -cell neogenesis. A few peptide agonists of GLP-1R have been brought to market in the past decade, but their clinical utility is limited by their short half-life, side effects and lack of oral bioavailability. A long asting, orally active small molecule drug for GLP-1R would significantly advance the state of the art in diabetes treatment. However, the development of such small molecule drugs has long been hindered by a lack of structural information about GLP-1R. The ultimate goal of this proposal is to obtain a high-resolution crystal structure of active-state GLP-1R in order to facilitate structue-based small molecule drug discovery. In Phase I, we will develop methods and tools to produce milligram quantities of high quality, active-state GLP-1R for crystallography studies that will be performed in Phase II. A major challenge in GPCR crystallization is to obtain large quantities of pure, stable receptor protein in its active-state, which in the case of GLP-1R is known to be unstable without additional stabilizing molecules. This proposal shows strong preliminary evidence that a novel method developed at ConfometRx enables us to form a stable GLP-1R-Gs protein complex in milligram quantities and at sufficient purity for crystallization. We will alo generate conformationally selective nanobodies that may further stabilize the GLP-1R-Gs complex or act as G protein surrogates to stabilize the active-state GLP-1R for crystallography. The major focus of Phase II is the crystallization and structure determination of active-state GLP-1R. We will pursue a comprehensive strategy to increase the chances of obtaining diffraction-quality crystals, such as crystallization in different lipid environments and crystal lattice contact enhancement by T4 lysozyme and nanobody techonologies. Once we have obtained the crystal structure of GLP1-R, it will allow us to perform in silico screening of small-molecule agonists or positive allosteric modulators. Novel lead compounds will be experimentally validated and subjected to structure-based optimization. Commercialization of this research will be achieved by providing data and services to pharmaceutical companies working on GLP-1R drugs. This proposal is in response to the NIDDK's RFA-DK-14-008, Reagents for Glucagon and Incretin Research.

Public Health Relevance

The glucagon-like peptide-1 receptor (GLP-1R) is an attractive drug target for type 2 diabetes. Several GLP-1R agonist peptides have been approved by FDA, but their use is limited by their short half-life and side effects as well as the fact that they have to be taken by injection due to their peptide nature. We propose to obtain a high-resolution crystal structure of GLP-1R in its active-state, which will facilitate structure-based drug discovery of novel non-peptide small molecule GLP-1R agonists as potential orally active drug candidates to treat type 2 diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
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Special Emphasis Panel (ZDK1)
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Arreaza-Rubin, Guillermo
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Confometrx, Inc.
Palo Alto
United States
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Zhang, Yan; Sun, Bingfa; Feng, Dan et al. (2017) Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein. Nature 546:248-253