Influenza, commonly called “flu”, is a contagious respiratory illness mainly caused by types A and B influenza viruses (FluAV, FluBV). Every year, FluAV (pdmH1N1 and H3N2 sub-types) and FluBV are responsible for up to 1 billion infections. Although most people generally fully recover, 3 to 5 million severe cases and 300,000 to 650,000 deaths are recorded every year, mainly people aged 65 years or older, and those younger than 2. As a consequence, influenza viruses are a recurrent health problem and a huge economic burden to our societies. In addition to annual epidemics, potentially devastating FluAV pandemics can occur at any time. In 1918, the famous “Spanish flu”, with a mortality rate of 2,5%, was responsible for 40 to 50 million deaths worldwide. Three more pandemics occurred since then: in 1957 (4 million deaths), in 1968 (2 million deaths) and in 2009 (280 000 deaths).
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.
