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PreprintCited by 8SARS-CoV-2 and COVID-19 ResearchProtease and Inhibitor MechanismsCOVID-19 Clinical Research Studies

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Trypstatin as a Novel TMPRSS2 Inhibitor with Broad-Spectrum Efficacy Against Corona and Influenza Viruses

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Lawrenz, Jan, Wettstein, Lukas, Alfonso, Armando Rodríguez, Nchioua, Rayhane, von Maltitz, Pascal, Albers, Dan P.J., Zech, Fabian, Vandeput, Julie, Naesens, Lieve, Fois, Giorgio, Preising, Nico, Schmierer, Emilia, Almeida-Hernandez, Yasser, Petersen, Moritz, Ständker, Ludger, Wiese, Sebastian, Braubach, Peter, Frick, Manfred, Barth, Eberhard, Sauter, Daniel, Kirchhoff, Frank, Sanchez-Garcia, Elsa, Stevaert, Annelies, Münch, Jan·2025·Advanced Science
DOI 10.1101/2025.01.14.632953PMC PMC12224939

Preprint — published as 10.1002/advs.202506430 · Paper page

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Abstract

Respiratory viruses, such as SARS-CoV-2 and influenza, exploit host proteases like TMPRSS2 for entry, making TMPRSS2 a prime antiviral target. Here, we report the identification and characterization of Trypstatin, a 61-amino acid Kunitz-type protease inhibitor derived from human hemofiltrate. Trypstatin inhibits TMPRSS2 and related proteases, with IC 50 values in the nanomolar range, comparable to the small molecule inhibitor camostat mesylate. In vitro assays demonstrated 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 reduced 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 reduced viral titers and alleviated clinical symptoms. These findings highlight Trypstatin’s potential as a broad-spectrum antiviral agent against TMPRSS2-dependent respiratory viruses. Abstract Figure:

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Metadata

Authors
Lawrenz, J., Wettstein, L., Alfonso, A. R., Nchioua, R., von Maltitz, P., Albers, D. P. J., Zech, F., Vandeput, J., Naesens, L., Fois, G., Preising, N., Schmierer, E., Almeida-Hernandez, Y., Petersen, M., Ständker, L., Wiese, S., Braubach, P., Frick, M., Barth, E., Sauter, D., Kirchhoff, F., Sanchez-Garcia, E., Stevaert, A., & Münch, J.
Affiliations
  • Universität Ulm (DE)
  • Rega Institute for Medical Research (BE)
  • Universitätsklinikum Tübingen (DE)
  • Medizinische Hochschule Hannover (DE)
  • University Hospital Ulm (DE)
Corresponding author
Münch, Jan
ORCID
Venue
Advanced Science
Publisher
openRxiv
Published
2025-01-15
Volume
12
Issue
25
Pages
e2506430-e2506430
ISSN
2198-3844 (ISSN-L)
DOI
10.1101/2025.01.14.632953
PMC
PMC12224939
OpenAlex
W4410373649
Cited by
8
References
89
Citations by year
2026: 4 · 2025: 4
FWCI
6.11
Type
journal article
Language
en
Open access
Licence
Locations
  • Advanced Science (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Lirias (submittedVersion, other-oa)
  • Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Baden-Württemberg Stiftung (CRC 1279, 436586093)
  • Deutsches Zentrum für Infektionsforschung (CRC1279, TI07.003)
  • Deutsche Forschungsgemeinschaft (CRC-1279, 390677874, EXC2033390677874, EXC2033, SA 2676/3‐1, CRC 1430, 436586093, 424228829)
  • Bundesministerium für Bildung und Forschung (CRC1279, 01KI20135)
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
Keywords
Kunitz-type inhibitor, SARS-CoV-2, influenza A virus, influenza B, SARS-CoV-1, MERS-CoV, HCoV-NL63, viral entry, spike protein, hemagglutinin, camostat mesylate, antiviral agents, airway epithelial cells, mucus, intranasal administration, Syrian hamster model, respiratory viruses
MeSH terms
COVID-19, SARS-CoV-2, COVID-19 Drug Treatment, Animals, Antiviral Agents, Cricetinae, Humans, Mesocricetus, Influenza A virus, Serine Endopeptidases, Virus Replication, Virus Internalization

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