Molecular Imaging of G-Protein-Coupled Receptors for Drug Development

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DESCRIPTION (provided by applicant): G-protein coupled receptors (GPCRs) transduce signals from the outside of cells, by binding to small molecules and their surrogates (drugs), to the inside where they trigger a cascade of events starting with interactions with G-proteins. There are 1000 different GPCRs in human genome, about 450 of which are potential drug targets. More than half of the currently available drugs interact with GPCRs. And since GPCRs are involved in a wide range of biological activities, e.g. blood pressure, pain, cancer growth, etc., the development of new drugs have the potential to cure or ameliorate the symptoms of many diseases. In order to accelerate the rational design of drugs, we propose to develop methods for determining the three dimensional structures of GPCRs. This is a substantial undertaking. On the path towards structure determination we will adapt NMR methods for screening for drug candidates that have been successfully applied to other classes of receptors. This research will be multidisciplinary, involving synthetic organic chemistry, molecular biology, structural biology, NMR spectroscopy, and computer calculations. This research will advance fundamental concepts of protein expression and NMR spectroscopy. It will be highly effective in training scientists that can interact across boundries. It requires the highest levels of technology available; as a result it, involves the University of California, San Diego and two leading biotechnology companies (ProSpect Pharma, Inc., Columbia, MD and m-phasys GmbH, Germany). ProSpect Pharma's key technology is isotopically labeled growth media and their effort is led by Jonathan Miles Brown, Ph.D., COO. M-phasys GmbH has developed methods for expressing GPCRs in bacteria that can utilize ProSpect Pharma's media, and refolding the proteins into their biologically active forms; their effort is led by Hans Kiefer Ph.D., CSO and Stefan Prytulla, Ph.D. GPCRs play a role in a number of human diseases due to their importance in maintaining proper function of living cells. Elucidation of the three-dimensional structures of GPCRs would enable us to look at this family of proteins at the atomic level, aiding in the understanding of how they function as well as how they interact with their respective ligands. This is therefore a very important step in helping to design drugs to target GPCR-related disorders that affect a large number of people including cancer, heart disease and obesity.