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.

开发针对病毒的新抗病毒治疗，尤其是由WHO散发出的高优先性和重新出现的病毒仍然至关重要，因为这些病毒在选择下进化。广谱宿主指导的抗病毒药物（HDA）是有前途的治疗选择，但是由于较低的一致性，因此通过较低的命中率，通过全基因组敲除筛查对相关宿主因素的强劲鉴定是有挑战性的。我们的项目旨在（1）建立计算和实验性管道，以识别和验证这些病毒的抗病毒药物，（2）至少识别一种针对WHO列出的潜在出现和重新出现病毒的广泛的抗病毒药物。 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与癌细胞系相比，从各种人体组织中获得的人体组织更适合研究宿主细胞生理，并且（iv）使用管道来识别宿主限制因子，当激活后，这些因素会挑战病毒。其次是基于小型激活RNA的创新药物开发和递送。该管道包括一个加急的臂，为此，将选择用于重新利用的广谱抗病毒药物，然后选择体外和体内疗效测试，以及临床试验作为概念证明。详细的手臂包括所有策略（i） - （iv），并将提供可持续的大流行准备管道，即准备运行，以确定在新爆发的早期针对新兴病毒的适当治疗方法。