TMPRSS2 inhibitors with broad-spectrum efficacy against SARS-CoV-2 (JN.1) and influenza A (H1N1) viruses protect mice from influenza A infection
Year: 2026
Type: article
Abstract: Human TMPRSS2 is a type II transmembrane serine protease and an essential host factor for SARS-CoV-2 and influenza A virus (IAV H1N1) infections. It facilitates the cleavage of viral surface glycoproteins, which are required for membrane fusion. This importance makes it an attractive target for host-directed antiviral therapies. We previously identified N-0385 and N-0920 as nanomolar TMPRSS2 inhibitors and demonstrated their antiviral potency against several SARS-CoV-2 variants. Here, we screened another twelve N-0385/N-0920 analogs with improved pharmacokinetics. Compounds 9 and 10 showed strong inhibition of TMPRSS2 activity and viral entry: they blocked pseudoviruses and authentic SARS-CoV-2 JN.1 and IAV H1N1 in Calu-3 cells. Compound 9 displayed a synergistic effect with baloxavir during IAV H1N1 infection. Both compounds highly reduced H1N1 infection in air–liquid interface cultures and mouse models, thus highlighting their broad antiviral potential. The discovery of broad-spectrum, host-directed antivirals against current and emerging human viruses is critical in preparing for future pandemics.
Source: Emerging Microbes & Infections
Authors: Lianne Presley, Jimena Pérez-Vargas, Anaïs Saintigny, Iván Villanueva, Michelle Ho, Jessica Fone, Lara Brinsden, Nidhi Kaushik, Syan Olver, Connor A. H. Thompson, Diana Bautista-Sánchez, Siobhan Ennis, Mike Chen, Matthew McCallum, Jack T. Brown, Sára Ferková, Brian Hetrick, David Veesler, Richard Leduc, Masahiro Niikura, Pierre-Luc Boudreault, Bryce Warner, François Jean
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,643
Funders: Burroughs Wellcome Fund, University of Washington, Faculty of Medicine, University of British Columbia, Innovation Saskatchewan, Canada Foundation for Innovation, University of British Columbia, National Institutes of Health, Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, National Institute of Allergy and Infectious Diseases, Government of Saskatchewan
OpenAlex ID: W7126237466