Role and modulation of host proteases involved in respiratory virus infections.

Respiratory viruses are adapted to spread within dense populations. This has been demonstrated notably by the influenza and SARS-CoV-2 pandemics, which cause influenza and COVID-19, respectively. Viruses cannot replicate autonomously; they rely on a host-in this case, respiratory tract cells-to which they must bind to initiate infection, thereby hijacking cellular components to produce and release new viral particles. Among these viruses, SARS-CoV-2, influenza, and human metapneumovirus share a similar entry mechanism that relies on enzymes found on the surface of respiratory tract cells. This commonality could be leveraged to develop an antiviral effective against all viruses dependent on this mechanism, representing a significant opportunity for preventing respiratory infections and pandemics. Our group has previously developed antivirals targeting these respiratory enzymes that successfully prevented the entry of SARS-CoV-2 and influenza. During my master's research, I investigated 135 derivatives of these molecules, leading to the discovery of compound N-0920, which is 35 times more effective against the recent SARS-CoV-2 variant JN.1. First, we will identify which enzymes facilitate the entry of these viruses. Concurrently, we will study the pharmacological behavior of these compounds within the respiratory system to determine their suitability for intranasal administration. Finally, the most promising compounds will be tested against viruses likely to be susceptible to the inhibition of these enzymes.