ArticleNature communications2025
Structural basis of TMPRSS11D specificity and autocleavage activation.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
10 citing papers in PubMed.
- Pockets to products: a data-driven approach for classification of monoterpene synthases.Digital discovery · 2026Article
- Discovery of Highly Selective Noncovalent Macrocyclic Peptide Inhibitors Suppressing Both TMPRSS2 Protease Activity and Viral Receptor Function.Journal of medicinal chemistry · 2026Article
- Hepatocyte growth factor activator inhibitor-2 rapidly inactivates airway-expressed human type II transmembrane serine proteases.The Journal of biological chemistry · 2026Article
- Native Metabolomics Unveils Suomilide Analogs with Potent Trypsin Inhibitory Activity.Journal of natural products · 2026Article
- Identification ofRSC medicinal chemistry · 2026Article
- HLA-DQB1-mediated B cell-epithelial crosstalk drives EBV-associated inflammation in Hunner-type interstitial cystitis.Molecular therapy. Nucleic acids · 2025Article
- TMPRSS11E-mediated TFR1 cleavage influences IFN-γR2 internalization and the macrophage innate response.Communications biology · 2025Article
- Large Library Docking and Biophysical Analysis of Small-Molecule TMPRSS2 Inhibitors.Journal of medicinal chemistry · 2025Article
- Ciliated cells promote high infectious potential of influenza A virus through the efficient intracellular activation of hemagglutinin.Journal of virology · 2025Article
- Host proteases: key regulators in viral infection and therapeutic targeting.Frontiers in immunology · 2025Review
Corrections and comments
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Authors and funding
18 authors.
Funding
Abstract
Transmembrane Protease, Serine-2 (TMPRSS2) and TMPRSS11D are human proteases that enable SARS-CoV-2 and Influenza A/B virus infections, but their biochemical mechanisms for facilitating viral cell entry remain unclear. We show these proteases spontaneously and efficiently cleave their own zymogen activation motifs, activating their broader protease activity on cellular substrates. We determine TMPRSS11D co-crystal structures with a native and an engineered activation motif, revealing insights into its autocleavage activation and distinct substrate binding cleft features. Leveraging this structural data, we develop nanomolar potency peptidomimetic inhibitors of TMPRSS11D and TMPRSS2. We show that a broad serine protease inhibitor that underwent clinical trials for TMPRSS2-targeted COVID-19 therapy, nafamostat mesylate, was rapidly cleaved by TMPRSS11D and converted to low activity derivatives. In this work, we develop mechanistic insights into human protease viral tropism and highlight both the strengths and limitations of existing human serine protease inhibitors, informing future drug discovery efforts targeting these proteases.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.