Periodic Reporting for period 1 - FluAttack (Validation of a novel antiviral drug candidate against influenza)
Période du rapport: 2020-04-01 au 2023-09-30
Our options to treat severe influenza cases and to respond to the next pandemic are currently extremely limited and all face the problem of viral resistance. We urgently need new and effective treatments against seasonal (FluAV and FluBV) and pandemic influenza. Moreover, these new strategies should reduce the risk of generating viral resistance.
We identified a family of molecules that showed a very strong inhibitory effect on FluAV replication in model cell lines without cytotoxicity. In particular, one compound went through several phase II and one phase III clinical trials against certain types of solid tumours, making this molecule a very attractive candidate for drug repurposing in the case of influenza virus infection. In addition, the mode of action of this compound is well documented: the molecule alters the function of a cellular protein complex used by all influenza viruses. Targeting a cellular co-factor as a therapeutic intervention against viruses is a new and attractive concept to reduce viral replication but also to minimize viral resistance.
In this context, the aim of FluAttack was to further characterise the antiviral activity of the compound against influenza viruses and to validate its activity in commercial 3D primary human airway epithelial cells (the natural target cells of the virus) and, if successful, in an in vivo animal model in order to then propose this molecule as an innovative drug candidate for the treatment of seasonal and pandemic influenza virus infections.
After a series of promising results in model cell lines and the characterisation of the active conformation of the compound, the results in primary human airway epitheliums were, unfortunately, disappointing. In contrast to model cell lines, we were not able to detect substantial antiviral activity in this relevant cellular system. As a consequence, the molecule was not tested in vivo.
Overall, this project highlighted the importance for the scientific community to work with relevant cellular systems such as primary cells or tissues early during antiviral drug development or even during drug screening/selection.
Drug repurposing is an attractive strategy, used for example by many scientists during the SARS-CoV-2 pandemic. However, one must be aware of the limitations of this approach, as we experienced in this study.