Antivirus Pandemic Preparedness EuropeAn pLatform (Appeal)

欧洲防病毒大流行准备平台（呼吁）

• 批准号: 10110329
• 金额: $ 60.54万
• 依托单位: IMPERIAL COLLEGE LONDON
• 依托单位国家: 英国
• 项目类别: EU-Funded
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=10110329
• 关键词: Antivirus; Pandemic; Preparedness; EuropeAn; pLatform

Developing new antiviral treatment against viruses and particularly high-priority emerging and re-emerging viruses aslisted by the WHO, remains crucial as, among other aspects, the viruses evolve under selection. Broad spectrum host-directed antiviral drugs (HDA) are promising therapeutic options, however the robust identification of relevant host factors by genome-wide knockout screens is challenging due to low consistency in the resulting hits. Our project aims to (1) establish a computational and experimental pipeline to identify and validate an antiviral for these viruses, and (2) identify at least one broad spectrum antiviral drug against potential emerging and re emerging viruses as listed by the WHO. To address these, we will implement a drug selection pipeline following several strategies: We will employ (i) machine learning, based on data from knockout screens, proteomics, protein interaction, transcriptomics of infected cells with pandemic-related viruses, Genome-Wide Association Studies, and generic gene descriptors, (ii) High Density Cell Arrays, which provide much more detailed readouts compared to state of the art pooled knockout screens, (iii) primary cell cultures obtained from a diverse array of human tissues, as they are more appropriate to study the host cell physiology during infection, compared to cancer cell lines, and (iv) use the pipeline to identify host restriction factors, which, when activated, challenge the virus; followed by innovative drug development and delivery based on small activating RNA. The pipeline comprises an Expedited Arm for which broad spectrum antiviral drugs for repurposing will be selected followed by in vitro and in vivo efficacy testing, and a clinical trial as a proof of concept. The elaborated Arm includes all strategies (i)-(iv) and will provide a sustainable pandemic preparedness pipeline ready-to-operate to identify the appropriate treatment against the emerging virus at the early time of a new outbreak.

针对病毒，特别是世界卫生组织列出的高度优先的新出现和重新出现的病毒，开发新的抗病毒治疗方法仍然至关重要，因为除其他方面外，病毒是在选择下进化的。广谱宿主抗病毒药物（HDA）是有前途的治疗选择，然而，由于所得命中的一致性较低，通过全基因组敲除筛选对相关宿主因子进行可靠识别具有挑战性。我们的项目旨在（1）建立一个计算和实验管道来识别和验证针对这些病毒的抗病毒药物，以及（2）识别至少一种针对世界卫生组织列出的潜在新出现和重新出现的病毒的广谱抗病毒药物。为了解决这些问题，我们将按照以下几种策略实施药物选择流程：我们将采用（i）机器学习，基于来自淘汰筛选、蛋白质组学、蛋白质相互作用、大流行相关病毒感染细胞的转录组学、全基因组协会的数据研究和通用基因描述符，(ii) 高密度细胞阵列，与最先进的混合敲除筛选相比，它提供更详细的读数，(iii) 从多种人体组织阵列中获得的原代细胞培养物，因为它们更适合学习与癌细胞系相比，感染期间的宿主细胞生理学，以及（iv）使用管道来识别宿主限制因子，这些因子在激活时会挑战病毒；其次是基于小激活 RNA 的创新药物开发和递送。该管道包括一个快速组，其中将选择用于重新利用的广谱抗病毒药物，然后进行体外和体内功效测试以及作为概念证明的临床试验。精心设计的 Arm 包括所有策略 (i)-(iv)，并将提供一个可随时投入使用的可持续大流行防范管道，以便在新疫情爆发的早期确定针对新出现的病毒的适当治疗方法。