Structure-based Drug Discovery for the GLP-1 Receptor

DESCRIPTION provided by applicant Glucagon like peptide receptor GLP R a member of family B G protein coupled receptors GPCRs is a highly attractive therapeutic target for type diabetes It has been shown clinically that the activation of GLP R 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 R 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 R 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 R The ultimate goal of this proposal is to obtain a high resolution crystal structure of active state GLP R 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 R 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 R 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 R 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 R Gs complex or act as G protein surrogates to stabilize the active state GLP R for crystallography The major focus of Phase II is the crystallization and structure determination of active state GLP R 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 T lysozyme and nanobody techonologies Once we have obtained the crystal structure of GLP 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 R drugs This proposal is in response to the NIDDKandapos s RFA DK andquot Reagents for Glucagon and Incretin Research andquot PUBLIC HEALTH RELEVANCE The glucagon like peptide receptor GLP R is an attractive drug target for type diabetes Several GLP R 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 R in its active state which will facilitate structure based drug discovery of novel non peptide small molecule GLP R agonists as potential orally active drug candidates to treat type diabetes