TMPRSS2 inhibitors with broad-spectrum efficacy against SARS-CoV-2 (JN.1) and influenza A (H1N1) viruses protect mice from influenza A infection
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Author(s)
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 Ferkováe, Brian Hetrick, David Veesler, Richard Leduc, Masahiro Niikura, Pierre-Luc Boudreault, Bryce Warner, and François Jean
This study describes two new compounds that inhibit human TMPRSS2, an enzyme in the host cell that viruses including SARS-CoV-2 and influenza A use to access the cell. The researchers tested a set of TMPRSS2 analogs in human lung cells and identified two molecules that effectively inhibited TMPRSS2 and stopped both a SARS-CoV-2 Omicron variant and the H1N1 influenza A virus from infecting the cells. The team treated the cells with one of these TMPRSS2 inhibitors along with an existing antiviral for influenza A and observed a synergistic effect. They then tested the TMPRSS2 inhibitors in mice infected with a lethal dose of the H1N1 virus and found that treatment with either compound significantly reduced viral levels in the lungs, prevented signs of clinical disease including weight loss, and greatly improved survival outcomes. This work provides crucial preclinical validation for TMPRSS2 inhibitors as potential influenza therapeutics and demonstrates that TMPRSS2 is an attractive target for broad-spectrum antiviral therapies.