Developing an efficient compound screening approach for the discovery of novel GPCR receptor antagonists

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A new drug takes an average 13.5 years and >US$1.8 billion before it reaches the market. The early phases of the process (screening, discovery, optimization, and preclinical studies) account for 46% of that cost, and take ~6 years. Hit identification and optimisation is frequently conducted by screening thousands of compounds using expensive and time-consuming cell-based assays to identify candidates for preclinical and clinical studies. In this project you will develop innovative approaches that reduce both cost and time of this screening step for a key class of protein targets, G-protein coupled receptors (GPCRs). GPCRs have been one of the most well exploited family of drug targets accounting for ~40% of all drugs currently on the market, but have remained one of the most challenging targets to drug, partly due to complications of working with membrane-bound proteins. You will use Styrene Maleic Acid Lipid Particle (SMALPs) polymers, to isolate membrane-bound GPCRs in their native environment and develop an efficient drug binding screen based on Fluorescence Correlation Spectroscopy (FCS) assays. As part of this project you will:1) Develop methods to efficiently express and purify functional SMALP encapsulated GPCRs (from the Calcitonin family). 2) Develop a high-throughput FCS assay for screening large compound libraries for binding to SMALP-GPCRs. 3) Use the assay to screen a focused library of ~3500 small molecules (available through Modulus Oncology Ltd), against the SMALP-GPCRs. You will receive expert training gaining a range of biomedical, biophysical and chemical skills, in addition to industrial and commercial experience working closely with two recent University spin out companies, Exciting Instruments and Modulus Oncology. Specifically, you will learn how to:1) encapsulate GPCRs in SMALPs (a method well established in Dr Richards' lab)2) develop FCS assays and single-molecule instrumentation (in Dr Craggs' lab)3) optimise a screening platform for novel hits, using fluorescent ligands (Prof Harrity's Lab)As such this project would suit a wide range of graduates from biochemistry, chemistry or physics, with relevant training tailored to your existing skill set. You will join a vibrant research environment working across three well-funded labs, with a focus on training the next generation of interdisciplinary researchers. You will be part of Single-molecules@ Sheffield (SM@Sh) a group of >10 like-minded research groups hosting regular seminars, problem solving sessions and social activities. Ultimately, your work on this project will likely lead to a new assay for drug discovery, and will prepare you equally well for an academic or industrial career, especially given the 3 month placement with Exciting Instruments and close working with Modulus Oncology as part of this iCASE studentship.