Determining the role of molecular co-chaperones in virus infection: a novel antiviral approach

背景资料。分子伴侣对于蛋白质的动态平衡是必不可少的，尤其是在癌症中。对于致癌病毒来说，分子伴侣是病毒蛋白折叠和稳定所必需的广泛宿主因子，因此病毒蛋白对分子伴侣相关途径的扰动非常敏感，为抗病毒提供了一个新的靶点。我们有令人兴奋的数据表明，分子辅助伴侣STIP1是KSHV复制所必需的。目标。本项目的目的是确定STIP1在KSHV生物学中的作用。我们将使用基于亲和力的定量蛋白质组学来定位KSHV-STIP1相互作用组。此外，该项目将利用药物化学方法来确定抑制分子辅助伴侣功能是否是治疗这一重要病毒家族的潜在治疗方法。在这里，我们将使用虚拟的高通量筛选活动来识别阻止STIP1功能的小分子抑制剂。然后将对优先考虑的化合物进行KSHV抗病毒活性筛选。因此，该项目将确定病毒对宿主分子伴侣途径的操纵如何在病毒感染期间调节病毒蛋白质组，并确定这是否是一种可行的抗病毒策略。新奇。这个项目非常新颖。分子伴侣是一个新兴的研究领域，对广泛病毒的复制至关重要。因此，该项目将研究病毒用来调节宿主细胞机制的新机制，这种机制可以决定如何调节病毒和宿主细胞蛋白质组，从而有利于病毒的复制。该项目是及时的，因为分子伴侣机制正在成为病毒复制的关键调节因素，因此它是一个有吸引力的抗病毒目标。此外，了解病毒如何操纵这一途径将提供更好的理解，即分子伴侣的变化如何与人类疾病相关。该项目采用了多学科方法和尖端方法，包括定量蛋白质组学、生物信息学分析、细胞生物学和药物化学。

Background. Molecular chaperones are essential for protein homeostasis, particularly in cancers. For oncogenic viruses, molecular chaperones function as broad host factors required for viral protein folding and stability, therefore viral proteins are exquisitely sensitive to perturbations in molecular chaperone-related pathways, presenting a novel antiviral target. We have exciting data showing that the molecular co-chaperone, STIP1, is essential for KSHV replication. Objectives. The aim of this project is to determine the role of STIP1 in KSHV biology. We will map the KSHV-STIP1 interactome using affinity-based quantitative proteomics. Moreover, the project will utilize a medicinal chemistry approach to determine if inhibiting molecular co-chaperone function is a potential therapeutic approach for the treatment of this important family of viruses. Here we will identify small molecule inhibitors which prevent STIP1 functioning, using a virtual high-throughput screening campaign. Prioritised compounds will then be screened for KSHV antiviral activity. Therefore this project will determine how virus-mediated manipulation of the host molecular chaperone pathway regulates the viral proteome during virus infection and determine if this is a viable antiviral strategy. Novelty. This project is highly novel. Molecular chaperones are an emerging area of research key to the replication of a wide range of viruses. The project will therefore investigate novel mechanisms utilised by viruses to regulate host cell machinery which can dictate how the virus and host cell proteome is regulated to benefit virus replication.Timeliness. The project is timely as the molecular chaperone machinery is emerging as a key regulator of virus replication, as such it is an attractive antiviral target. Moreover, understanding how viruses manipulate this pathway will provide a better understanding of how alterations in molecular chaperones are associated with human disease.Experimental Approach. The project utilises a multidisiplinary approach and cutting-edge methodology including quantitiative proteomics, bioinformatic analysis, cell biology and medicinal chemistry.