Identification of <i>p</i> -aminobenzylamine derivatives as dual non-covalent inhibitors of the transmembrane host proteases TMPRSS2 and HAT proteases with anti-viral potential
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 <i>para</i>-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.
Authors
- Feryel Soualmia (ORCID: https://orcid.org/0000-0003-1818-703X)
- Chahrazade El Amri (ORCID: https://orcid.org/0000-0002-1028-5113)
- Nancy Chaaya
- Nicolas Masurier (ORCID: https://orcid.org/0000-0001-9169-8149)
- Saadou Kadri
- Ashok Dussol
- Hélène Carvaillo
Institutions
- École Nationale Supérieure de Chimie de Montpellier (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université de Montpellier (FR)
- Sorbonne Université (FR)
- Institut de Biologie Paris-Seine (FR)
- Institut des Biomolécules Max Mousseron (FR)
- Développement Adaptation et Vieillissement (FR)
Publication Details
- Journal
- RSC Medicinal Chemistry
- Published
- 2025-10-28
- DOI
- https://doi.org/10.1039/d5md00680e
- Primary Topic
- Computational Drug Discovery Methods
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Infrastructures en Biologie Santé et Agronomie
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Centre National de la Recherche Scientifique
- Université de Montpellier
- Sorbonne Université