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

一种新药进入市场平均需要13.5年，耗资18亿美元。该过程的早期阶段（筛选、发现、优化和临床前研究）占该成本的46%，耗时约6年。Hit鉴定和优化通常是通过筛选数千种化合物来进行的，这些化合物使用昂贵且耗时的基于细胞的测定来确定临床前和临床研究的候选化合物。在这个项目中，你将开发创新的方法，降低筛选关键蛋白质靶点g蛋白偶联受体（gpcr）的成本和时间。gpcr是目前市场上所有药物中利用最充分的靶点之一，占40%，但仍然是最具挑战性的药物靶点之一，部分原因是与膜结合蛋白一起工作的并发症。您将使用苯乙烯马来酸脂质颗粒（SMALPs）聚合物，在其天然环境中分离膜结合的gpcr，并基于荧光相关光谱（FCS）分析开发有效的药物结合筛选。作为该项目的一部分，您将：1)开发有效表达和纯化功能性SMALP封装gpcr的方法（来自降钙素家族）。2)开发一种高通量FCS试验，用于筛选与small - gpcr结合的大化合物文库。3)使用该方法筛选约3500个小分子的集中文库（可通过Modulus Oncology Ltd获得），以对抗small - gpcr。您将接受专业培训，获得一系列生物医学，生物物理和化学技能，以及与两家最近的大学分拆公司，Exciting Instruments和Modulus Oncology密切合作的工业和商业经验。具体来说，您将学习如何：1)在SMALPs中封装gpcr（在Richards博士的实验室中建立了一种方法）2)开发FCS检测和单分子仪器（在Craggs博士的实验室中）3)使用荧光配体优化新靶点的筛选平台（Harrity教授的实验室）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，重点是培养下一代跨学科研究人员。您将成为Single-molecules@ Sheffield （SM@Sh）的一员，该组织由bbb10个志同道合的研究小组组成，定期举办研讨会，解决问题会议和社交活动。最终，你在这个项目中的工作可能会导致一种新的药物发现分析，并将为你的学术或工业生涯做好准备，特别是考虑到在Exciting Instruments工作3个月，并与Modulus Oncology密切合作，作为iCASE学生的一部分。

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.