RATIONAL DESIGN OF COUMARIN DERIVATIVES WITH A BASIC MOIETY FOR INHIBITING THE SERINE PROTEASE TMPRSS2: AN INNOVATIVE APPROACH TO COMBAT THE ENTRY OF SELECTED RESPIRATORY VIRUSES

The recent global pandemic caused by the new coronavirus, SARS-CoV-2, has underscored the urgent need to develop effective antiviral treatments, given the continuing risk of future viral pandemics. A key focus for this innovative research is the human serine protease TMPRSS2, which is closely involved in the entry mechanisms of some respiratory viruses.
Our research adopts a rational approach, investigating the synthesis of substituted coumarin derivatives as potential antiviral agents. Preliminary in vitro and in silico results from our chemical library suggest that coumarin derivatives may hold promise as inhibitors of TMPRSS2. Activity assays on the purified enzyme as well as docking experiments highlight the pharmacomodulations necessary to enhance activity and selectivity for TMPRSS2. These include the substitution of coumarinic derivatives with a basic functional group and the presence of a leaving group at the 6-position of the coumarin ring.
To gain information on the selectivity and activity of these compounds and guide our drug design, tests with isolated enzymes along with a comprehensive evaluation of the cytotoxicity of these derivatives are planned. Finally, these new compounds will be tested against various viral strains to assess their antiviral activity.
This multidisciplinary approach aims to identify promising antiviral agents that will broaden therapeutic options against respiratory diseases and potentially play a fundamental role in the prevention and management of future pandemics.