APPEAL

Abstract:

Developing new antiviral treatment against viruses and particularly high-priority emerging and re-emerging viruses as listed by the WHO, remains crucial as, among other aspects, the viruses evolve under selection. Broad spectrum hostdirected 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.

Leitat’s Role in the Project:

Leitat’s primary role and contribution to the project focuses on the several capabilities from target identification up to preclinical studies, including medicinal and analytical chemistry, in vitro and in vivo pharmacology, drug metabolism and pharmacokinetics, and toxicology. APPEAL project covers broad areas of pharmaceutical research of animal models, in vitro and in vivo techniques, and clinical samples bioanalysis. We will participate in the target selection (WP4; partner), drug development and selection (WP5; partner), drug in vitro and in vivo testing (WP6; partner), grant and project management (WP8; partner), and dissemination, communication, and exploitation (WP9; partner).