ArticleProceedings of the National Academy of Sciences of the United States of America2021
A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells.
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Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 84 papers, 1 of them a synthesis that pooled it.
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84citing papers in PubMed, 1 pooled it
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Who cites it
84 citing papers in PubMed, 1 synthesis or guideline pooled it, 115 citations in OpenAlex.
- Newly Emerged Antiviral Strategies for SARS-CoV-2: From Deciphering Viral Protein Structural Function to the Development of Vaccines, Antibodies, and Small Molecules.International journal of molecular sciences · 2022Pooled it
- One Week of Oral Camostat Versus Placebo in Nonhospitalized Adults With Mild-to-Moderate Coronavirus Disease 2019: A Randomized Controlled Phase 2 Trial.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2023Trial
- Identification of Four Compounds with S-RBD-Binding and Pseudovirus Entry-Inhibitory Activity.International journal of molecular sciences · 2026Article
- Discovery of Highly Selective Noncovalent Macrocyclic Peptide Inhibitors Suppressing Both TMPRSS2 Protease Activity and Viral Receptor Function.Journal of medicinal chemistry · 2026Article
- Artificial intelligence and ultra-high performance computing methods and experiments for drug discovery: virtual screening, deep learning, molecular dynamics simulations, ADMET modelling, and experimental validation.Molecular biomedicine · 2026Review
- Recent Advances in the Design of Inhibitors Targeting the Viral Entry and Replication of the SARS-CoV-2 Virus, Driven by In Silico Approaches.Molecules (Basel, Switzerland) · 2026Review
- Deadbolt Drug Discovery: Locking the Door to Class 1 Viral Entry by Small Molecules.ACS infectious diseases · 2026Review
- Hepatocyte growth factor activator inhibitor-2 rapidly inactivates airway-expressed human type II transmembrane serine proteases.The Journal of biological chemistry · 2026Article
- Bulkiness Makes the Difference: Modulating Solid-State Emission of Anticoronavirus Active Pt(tpy)C(O)NHCH2R Complexes Featuring Adamantyl vs Propargyl R Groups.Inorganic chemistry · 2026Article
- Addressing the zoonotic threat of merbecoviruses.Nature microbiology · 2026Review
- Lock out: targeting TMPRSS2 to block influenza and coronaviruses.Journal of virology · 2026Review
- Broad-acting antivirals: the pursuit of pan-viral therapeutics in the era of pandemics.Journal of virology · 2026Review
- Epithelial TMPRSS2 impairs glucose homeostasis in obese mice by regulating ghrelin-GLP-1 receptor signaling pathway.JCI insight · 2026Article
- TMPRSS2-mediated coronavirus spike activation and inhibition.Nature structural & molecular biology · 2026Article
- 3-Amidinophenylalanine-Derived Inhibitors' Antiviral Effect Against H1N1 Influenza A Virus.Antibiotics (Basel, Switzerland) · 2026Article
- Mucosal IL-36 is a defining feature of severe paediatric bronchiolitis.Mucosal immunology · 2026Article
- Structural Basis of Serine Protease Inhibition by Antibodies from Biased Fab Phage-Display Libraries.bioRxiv : the preprint server for biology · 2026Article
- Identification ofRSC medicinal chemistry · 2026Article
- Efficient production of fully active, SARS-CoV-2-priming, wildtype TMPRSS2 ectodomain via co-expression of HAI-2 allows for both auto- and cross-activation mechanisms.The Biochemical journal · 2025Article
- Development of ketobenzothiazole-based peptidomimetic TMPRSS13 inhibitors with low nanomolar potency.Journal of enzyme inhibition and medicinal chemistry · 2025Article
24 more citing papers are in PubMed but not listed here.
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Authors and funding
23 authors at 6 institutions in 2 countries.
Matthew MahoneyDepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO 63110.ORCID 0000-0003-3191-2128
Vishnu C DamalankaDepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO 63110.ORCID 0000-0002-1946-1320
Michael A TartellDepartment of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110.ORCID 0000-0002-4518-4187
Dong Hee ChungDepartment of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158.
André Luiz LourençoDepartment of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158.
Dustin PweeSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093.ORCID 0000-0003-4692-8640
Anne E Mayer BridwellDepartment of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110.
Markus HoffmannInfection Biology Unit, German Primate Center, Leibniz Institute for Primate Research, Göttingen 37077, Germany.ORCID 0000-0003-4603-7696
Jorine VossDepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO 63110.ORCID 0000-0003-2139-4179
Partha KarmakarDepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO 63110.
Nurit P AzouzDivision of Allergy and Immunology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229.ORCID 0000-0003-4969-1263
Andrea M KlinglerDivision of Allergy and Immunology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229.
Paul W RothlaufDepartment of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110.ORCID 0000-0002-0941-4467
Cassandra E ThompsonDepartment of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110.ORCID 0000-0001-6273-8113
Melody LeeDepartment of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158.
Lidija KlampferProteXase Therapeutics, Inc., Saint Louis, MO 63108.
Christina L StallingsDepartment of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110.ORCID 0000-0002-2747-5618
Marc E RothenbergDivision of Allergy and Immunology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229.
Stefan PöhlmannInfection Biology Unit, German Primate Center, Leibniz Institute for Primate Research, Göttingen 37077, Germany.ORCID 0000-0001-6086-9136
Sean P J WhelanDepartment of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110.ORCID 0000-0003-1564-8590
Anthony J O'DonoghueSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093.ORCID 0000-0001-5695-0409
Charles S CraikDepartment of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158.ORCID 0000-0001-7704-9185
James W JanetkaDepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO 63110; janetkaj@wustl.edu.
Washington University in St. Louis · USUniversity of California, San Francisco · USCincinnati Children's Hospital Medical Center · USGerman Primate Center · DEHarvard University · USUniversity of California San Diego · US
Funding
Washington University Center for Cellular ImagingP30CA091842 · NCI · WASHINGTON UNIVERSITY · PI TIMOTHY J. EBERLEIN · 2001 to 2026
$128.0MRP5: Chemical proteomic discovery of small-molecule probes for autophagy proteinsU19AI142784 · NIAID · UT SOUTHWESTERN MEDICAL CENTER · PI VIRGIN, HERBERT W · 2019 to 2023
$36.9MTSLP, IL-9-producing mucosal mast cells, and allergic inflammationU19AI070235 · NIAID · CINCINNATI CHILDRENS HOSP MED CTR · PI Gurjit K. Khurana Hershey · 2006 to 2026
$31.3MX-ray Screening and Rapid Structure DeterminationP50AI150476 · NIAID · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI EMERMAN, MICHAEL · 2019 to 2021
$14.4MMolecular and Cellular Mechanisms in CancerT32CA108462 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI GOGA, ANDREI · 2004 to 2024
$10.4MTraining Program in Cellular and Molecular BiologyT32GM139774 · NIGMS · WASHINGTON UNIVERSITY · PI HEATHER L TRUE-KROB · 2021 to 2026
$6.7MTargeting Hepatocyte Growth Factor Processing and Activation in Lung CancerR43CA224832 · NCI · PROTEXASE THERAPEUTICS, INC. · PI JANETKA, JAMES W, KLAMPFER, LIDIJA · 2018 to 2018
$300kInhibitors of pro‐HGF activation overcome resistance to anti‐EGFR therapyR43CA243941 · NCI · PROTEXASE THERAPEUTICS, INC. · PI JANETKA, JAMES W, KLAMPFER, LIDIJA · 2019 to 2019
$300kNCI NIH HHS P30 CA091842NCI NIH HHS R43 CA224832NCI NIH HHS R43 CA243941NCI NIH HHS T32 CA108462NIAID NIH HHS P50 AI150476NIAID NIH HHS U19 AI070235NIAID NIH HHS U19 AI142784NIGMS NIH HHS T32 GM139774Wellcome Trust
Abstract
The host cell serine protease TMPRSS2 is an attractive therapeutic target for COVID-19 drug discovery. This protease activates the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and of other coronaviruses and is essential for viral spread in the lung. Utilizing rational structure-based drug design (SBDD) coupled to substrate specificity screening of TMPRSS2, we have discovered covalent small-molecule ketobenzothiazole (kbt) TMPRSS2 inhibitors which are structurally distinct from and have significantly improved activity over the existing known inhibitors Camostat and Nafamostat. Lead compound MM3122 (4) has an IC
Indexed as
COVID-19 Drug TreatmentAnimalsBenzamidinesBenzothiazolesCell LineCOVID-19Drug DesignEpithelial CellsEstersGuanidinesHumansLungMiceMiddle East Respiratory Syndrome CoronavirusOligopeptidesSARS-CoV-2Ac-GQFR-kbtBenzamidinesbenzothiazoleBenzothiazolescamostatEstersGuanidinesnafamostatOligopeptidesSerine EndopeptidasesSmall Molecule LibrariesTMPRSS2 protein, humanantiviralCOVID-19protease inhibitorPS-SCLstructure-based drug discovery
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