Developing New Antiviral Treatment Against Emerging and Re-emerging Viruses: APPEAL Project

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 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 reemerging 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 tasks

Leitat will participate in the target selection (WP4 partner), drug development and selection (WP5 partner), drug in vitro and in vivo testing (WP6 leader), grant and project management (WP8 partner), and dissemination, communication, and exploitation (WP9 partner)

More precisely, Leitat is responsable of the virtual screening for compounds identification and subsequent synthesis/procurement of the compound libraries. Afterwards, LEITAT will also lead the in-vitro assays (such as ADME-Tox, solubility, permeability and citotoxicity) for compound profiling and lead selection.

Later on, Leitat will be in charge of the drug in-vivo testing, which will be carried in rodent models. The activities that Leitat leads are the efficacy studies, pharmacokinetics and PK/PD relationships

Main Mission

APPEAL project aims to establish a computational and experimental pipeline to identify and validate an antiviral for these viruses, and to identify at least one broad spectrum antiviral drug against potential emerging and re-emerging viruses as listed by the World Health Organization.

To achieve these objective, APPEAL will implement a drug selection pipeline following a high-tech strategy employing 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, High Density Cell Arrays, which provide much more detailed readouts compared to state of the art pooled knockout screens, 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, anduse 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.

Consortium