Identification of p-aminobenzylamine derivatives as dual non-covalent inhibitors of the transmembrane host proteases TMPRSS2 and HAT proteases with anti-viral potential

Abstract

TMPRSS2 and HAT (or TMPRSS11D) are host serine proteases critically involved in the entry of several respiratory viruses, including SARS-CoV-2. To our knowledge, no dual inhibitors targeting both enzymes have been reported to date. Here, we describe a series of para-aminobenzylamine derivatives acting as potent dual TMPRSS2/HAT non-covalent inhibitors. In SARS-CoV-2 infection assays in lung epithelial cells, four compounds demonstrated significant antiviral activity without cytotoxicity at tested doses. Drug-likeness profiling confirmed compliance with Lipinski's and Veber's rules, as well as favourable solubility and microsomal stability. These findings highlight a novel chemical series with potential as broad-spectrum antivirals targeting host proteases.