Design of original serine protease inhibitors to combat viral respiratory infections: a synthetic pathway for new coumarinic compounds

Since the emergence of the Covid-19 pandemic, it has become imperative to search for new antivirals that could be used for viral respiratory infections. The risk of future pandemics remains high, requiring the development of broad-spectrum antivirals.
Our study focuses on the human serine protease enzyme, more particularly transmembrane serine protease 2 (TMPRSS2), which is known to play a crucial role in the entry mechanism of certain viruses, such as Influenza A and coronaviruses responsible for severe acute respiratory syndromes. The development of inhibitors targeting this enzyme represents a breakthrough in the treatment of viral respiratory infections.
Preliminary in vitro results obtained with the isolated enzyme and SARS-CoV-2 virus suggest that coumarinic compounds from our chemical library hold a significant promise as a starting point for the development of TMPRSS2 inhibitors. A thorough examination of the coumarin core structure has highlighted the potential for pharmacomodulation of this ring system. Concurrently, in silico docking techniques have facilitated the rational design and the development of new serine protease inhibitors with enhanced selectivity for TMPRSS2. This approach aims to introduce a cationic substituent ranging from 0 to 2 carbons onto the phenyl ring, thereby promoting a strong ionic interaction with Asp435 located within the catalytic pocket. This modification is expected to significantly improve the activity and selectivity of new synthetic compounds against TMPRSS2.