FROM COUMARIN TO ANTIVIRAL INHIBITORS: TARGETING TMPRSS2 AND HAT IN THE TREATMENT OF VIRAL RESPIRATORY INFECTIONS

The global pandemic caused by the SARS-CoV-2 coronavirus has highlighted the urgent need to develop new antiviral treatments, particularly for respiratory infections. In this context, transmembrane serine protease type 2 (TMPRSS2), which is involved in the entry mechanism of several viruses, including SARS-CoV-2, is a key target. Human Airway Trypsin-Like Protease (HAT), TMPRSS11D, that also allows to facilitate virus entry and participates to the inflammatory response in lung, constitutes an emerging target.

Our research focuses on the design of coumarin-3-carboxylic acid derivatives as inhibitors of these two transmembrane serine proteases. The aim is to explore the synthesis of substituted 3-phenoxycarbonyl ester derivatives and to assess their inhibitory activity against TMPRSS2 and HAT. We are particularly interested in introducing basic groups into the structure to maximize the selective inhibition of these proteases.

We have synthesized a series of derivatives bearing basic groups at different positions relative to the phenyl ring and also modulated the leaving groups present at the 6-position (i.e. chloromethyl and acetoxymethyl groups). These compounds were evaluated in enzymatic assays to quantify their inhibitory activity against TMPRSS2 and HAT.
In addition, their potential cytotoxic effect was assessed on several cell lines, including embryonic lung cells to select the most pertinent hit compounds.

First results indicate that several coumarin derivatives show promising inhibitory activity against TMPRSS2 and HAT and most these hit derivatives were found non-toxic, indicating good therapeutic potential. In terms of stability, our tests showed that more neutral conditions improved the stability of certain derivatives.

Further studies are ongoing to better characterize the inhibition mechanisms and to refine pharmacomodulations to design second-generation of compounds. We will also extend testing by evaluating their antiviral potential against different viral strains, including SARS-CoV-2, to assess their efficacy.
In conclusion, we succeed in highlighting the potential of coumarin derivatives to inhibit TMPRSS2 and HAT, proposing thus a novel family of compounds with varied mechanisms of inhibition in the treatment of respiratory infections and the management of future pandemics.