Antivirus Pandemic Preparedness EuropeAn pLatform (Appeal)

开发新的抗病毒治疗，特别是WHO列出的高度优先的新出现和重新出现的病毒，仍然至关重要，因为除其他方面外，病毒在选择下进化。广谱宿主定向抗病毒药物（HDA）是有前途的治疗选择，然而，由于所得命中的低一致性，通过全基因组敲除筛选来稳健地鉴定相关宿主因子是具有挑战性的。我们的项目旨在（1）建立一个计算和实验管道，以确定和验证这些病毒的抗病毒药物，（2）确定至少一种广谱抗病毒药物，以对抗WHO列出的潜在新出现和重新出现的病毒。为了解决这些问题，我们将实施以下几种策略的药物选择管道：我们将采用（i）机器学习，基于来自敲除筛选，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，全基因组关联研究和通用基因描述符的数据，（ii）高密度细胞阵列，其提供了比现有技术的合并敲除筛选更详细的读数，（iii）从多种人类组织获得的原代细胞培养物，因为它们更适合于研究感染期间的宿主细胞生理学，与癌细胞系相比，以及（iv）使用管道来识别宿主限制因子，当激活时，挑战病毒;然后是基于小激活RNA的创新药物开发和交付。该管道包括一个加速组，将选择用于再利用的广谱抗病毒药物，然后进行体外和体内疗效测试，并进行临床试验作为概念验证。详细制定的应急机制包括所有战略（i）-（iv），并将提供一个可持续的大流行防备渠道，随时可以运作，以便在新的疫情爆发初期确定针对新出现病毒的适当治疗方法。

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.