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

一种新药平均需要13.5年和18亿美元才能上市。该过程的早期阶段(筛选、发现、优化和临床前研究)占成本的46%，耗时约6年。HIT鉴定和优化通常通过使用昂贵且耗时的基于细胞的分析来筛选数千种化合物来进行，以确定临床前和临床研究的候选者。在这个项目中，您将开发创新的方法，以减少对一类关键的蛋白质靶标--G蛋白偶联受体(GPCRs)--的筛选步骤的成本和时间。GPCRs是开发最充分的药物靶标家族之一，约占目前市场上所有药物的40%，但仍是最具挑战性的药物靶标之一，部分原因是与膜结合蛋白的复杂工作。您将使用苯乙烯马来酸脂质颗粒(SMALP)聚合物，在其天然环境中分离膜结合的GPCRs，并开发基于荧光相关光谱(FCS)分析的高效药物结合筛选。作为该项目的一部分，您将：1)开发高效表达和纯化功能性SMALP包裹的GPCRs(来自降钙素家族)的方法。2)建立高通量FCS方法，用于筛选与SMALP-GPCRs结合的大型化合物文库。3)使用该方法筛选针对SMALP-GPCRs的~3500个小分子的聚焦文库(可从Modulus Oncology Ltd获得)。你将接受专家培训，获得一系列的生物医学、生物物理和化学技能，此外还有与最近两家大学衍生公司--激励仪和Modulus Oncology--密切合作的工商业经验。具体地说，您将学习如何：1)将GPCRs封装在SMALP中(这是Richards博士的实验室已经很好地建立的方法)2)开发FCS分析和单分子仪器(在Craggs博士的实验室)3)使用荧光配体(Harrity教授的实验室)优化新的Hit的筛选平台因此该项目将适合广泛的生物化学、化学或物理毕业生，并根据您现有的技能进行相关培训。你将加入一个充满活力的研究环境，在三个资金充足的实验室工作，专注于培训下一代跨学科的研究人员。你将成为单分子@谢菲尔德(SM@Sh)的一员，这是一个由10个志同道合的研究小组组成的小组，定期举办研讨会、解决问题的会议和社会活动。最终，你在这个项目上的工作可能会带来一种新的药物发现方法，并将为你的学术或工业职业生涯做好同样好的准备，特别是考虑到作为这一iCASE学生的一部分，你将与令人兴奋的仪器一起工作3个月，并与模块肿瘤学密切合作。

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.