RATIONAL DESIGN OF COUMARIN DERIVATIVES AS NEW INHIBITORS OF TRANSMEMBRANE SERINE PROTEASES TO TREAT RESPIRATORY VIRAL INFECTIONS

The COVID-19 pandemic has highlighted the urgent need to develop new
antivirals to treat emergent respiratory infections. As a promising approach to
combat SARS-CoV-2 and other respiratory viral infections, we designed and
evaluated novel inhibitors of the Transmembrane Serine Protease 2 (TMPRSS2),
as well as Human Airway trypsin-like protease (HAT; TMPRSS11D), host surface
serine proteases involved in viral cell penetration and associated inflammatory
responses.
In vitro results first obtained with compounds from our chemical library suggest
that appropriately substituted phenyl esters of coumarin-3-carboxylic acid are
TMPRSS2 inhibitors. Based on molecular modeling, we then rationally
synthesized new coumarin derivatives bearing different basic groups at various
positionsrelative to the phenyl ring. In addition, several leaving groups, including
chloromethyl and acetoxymethyl moieties at the 6-position of the coumarin
cycle, were introduced. The compounds inhibitory activities on TMPRSS2 and
HAT were evaluated using appropriate enzymatic assays. Noticeable efficiency
and selectivity were observed for several compounds. Cytotoxicity tests in
human embryonic lung cells showed no cytotoxicity for most compounds. Our
next steps will be to fully evaluate the antiviral potential of our candidates to a
larger set of viruses. Finally, their detailed inhibition mechanisms will be
thoroughly investigated to guide the further development/optimization of these
new antiviral agents aiming to treat respiratory diseases.