Trypstatin as a Novel TMPRSS2 Inhibitor with Broad‐Spectrum Efficacy against Corona and Influenza Viruses
Respiratory viruses, such as SARS-CoV-2 and influenza, exploit host proteases like TMPRSS2 for entry, making TMPRSS2 a prime antiviral target. Here, the identification and characterization of Trypstatin, a 61-amino acid Kunitz-type protease inhibitor derived from human hemofiltrate are reported. Trypstatin inhibits TMPRSS2 and related proteases with high potency, exhibiting half-maximal inhibitory concentration values in the nanomolar range, comparable to the small molecule inhibitor camostat mesylate. In vitro assays demonstrate that Trypstatin effectively blocks spike-driven entry of SARS-CoV-2, SARS-CoV-1, MERS-CoV, and hCoV-NL63, as well as hemagglutinin-mediated entry of influenza A and B viruses. In primary human airway epithelial cultures, Trypstatin significantly reduces SARS-CoV-2 replication and retained activity in the presence of airway mucus. In vivo, intranasal administration of Trypstatin to SARS-CoV-2-infected Syrian hamsters reduces viral titers and alleviates clinical symptoms. These findings highlight Trypstatin's potential as a broad-spectrum antiviral agent against TMPRSS2-dependent respiratory viruses.
Authors
- Ludger Ständker
- Julie Vandeput (ORCID: https://orcid.org/0000-0003-3554-1088)
- Rayhane Nchioua (ORCID: https://orcid.org/0009-0001-1436-1232)
- Peter Braubach (ORCID: https://orcid.org/0000-0003-3673-7779)
- Dan Albers (ORCID: https://orcid.org/0000-0002-5863-6322)
- Fabian Zech (ORCID: https://orcid.org/0000-0002-1668-8060)
- Manfred Frick (ORCID: https://orcid.org/0000-0002-4763-1104)
- Sebastian Wiese (ORCID: https://orcid.org/0000-0001-5697-2608)
- Daniel Sauter (ORCID: https://orcid.org/0000-0001-7665-0040)
- Jan Lawrenz (ORCID: https://orcid.org/0000-0003-3767-7130)
- Armando Rodríguez (ORCID: https://orcid.org/0000-0001-5921-3770)
- Annelies Stevaert (ORCID: https://orcid.org/0000-0003-3316-2826)
- Elsa Sánchez‐García (ORCID: https://orcid.org/0000-0002-9211-5803)
- Pascal von Maltitz (ORCID: https://orcid.org/0000-0003-0533-6999)
- Giorgio Fois (ORCID: https://orcid.org/0000-0001-5414-1149)
- Jan Münch (ORCID: https://orcid.org/0000-0001-7316-7141)
- Lukas Wettstein (ORCID: https://orcid.org/0000-0002-8182-9309)
- Frank Kirchhoff (ORCID: https://orcid.org/0000-0002-7052-2360)
- Yasser Almeida‐Hernández (ORCID: https://orcid.org/0000-0001-9832-3534)
- Nico Preising
- Moritz Petersen (ORCID: https://orcid.org/0000-0003-2046-848X)
- Lieve M. J. Naesens (ORCID: https://orcid.org/0000-0001-9742-9302)
- Eberhard Barth
- Emilia Schmierer
- Veronika Neubauer
Institutions
- Universität Ulm (DE)
- TU Dortmund University (DE)
- Rega Institute for Medical Research (BE)
- Medizinische Hochschule Hannover (DE)
- Institute of Medical Microbiology and Hygiene (DE)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-05-14
- DOI
- https://doi.org/10.1002/advs.202506430
- Citations
- 5
- Primary Topic
- Influenza Virus Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 6.77
Funders
- Baden-Württemberg Stiftung
- Deutsches Zentrum für Infektionsforschung
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung