A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells


Posted: 2021-10-12 19:00:00
Proc Natl Acad Sci U S A . 2021 Oct 26;118(43):e2108728118. doi: 10.1073/pnas.2108728118. Matthew Mahoney 1 2 , Vishnu C Damalanka 1 , Michael A Tartell 3 4 , Dong Hee Chung 5 , André Luiz Lourenço 5 , Dustin Pwee 6 , Anne E Mayer Bridwell 3 , Markus Hoffmann 7 8 , Jorine Voss 1 , Partha Karmakar 1 , Nurit P Azouz 9 , Andrea M Klingler 9 , Paul W Rothlauf 3 4 , Cassandra E Thompson 3 , Melody Lee 5 , Lidija Klampfer 2 , Christina L Stallings 3 , Marc E Rothenberg 9 , Stefan Pöhlmann 7 8 , Sean P J Whelan 3 , Anthony J O'Donoghue 6 , Charles S Craik 5 , James W Janetka 10 2 Affiliations Expand Affiliations 1 Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO 63110. 2 ProteXase Therapeutics, Inc., Saint Louis, MO 63108. 3 Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110. 4 Program in Virology, Harvard Medical School, Boston, MA 02115. 5 Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158. 6 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093. 7 Infection Biology Unit, German Primate Center, Leibniz Institute for Primate Research, Göttingen 37077, Germany. 8 Faculty of Biology and Psychology, Georg-August University Göttingen, Göttingen 37077, Germany. 9 Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229. 10 Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO 63110; janetkaj@wustl.edu. Item in Clipboard Matthew Mahoney et al. Proc Natl Acad Sci U S A. 2021. Show details Display options Display options Format Proc Natl Acad Sci U S A . 2021 Oct 26;118(43):e2108728118. doi: 10.1073/pnas.2108728118. Authors Matthew Mahoney 1 2 , Vishnu C Damalanka 1 , Michael A Tartell 3 4 , Dong Hee Chung 5 , André Luiz Lourenço 5 , Dustin Pwee 6 , Anne E Mayer Bridwell 3 , Markus Hoffmann 7 8 , Jorine Voss 1 , Partha Karmakar 1 , Nurit P Azouz 9 , Andrea M Klingler 9 , Paul W Rothlauf 3 4 , Cassandra E Thompson 3 , Melody Lee 5 , Lidija Klampfer 2 , Christina L Stallings 3 , Marc E Rothenberg 9 , Stefan Pöhlmann 7 8 , Sean P J Whelan 3 , Anthony J O'Donoghue 6 , Charles S Craik 5 , James W Janetka 10 2 Affiliations 1 Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO 63110. 2 ProteXase Therapeutics, Inc., Saint Louis, MO 63108. 3 Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110. 4 Program in Virology, Harvard Medical School, Boston, MA 02115. 5 Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158. 6 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093. 7 Infection Biology Unit, German Primate Center, Leibniz Institute for Primate Research, Göttingen 37077, Germany. 8 Faculty of Biology and Psychology, Georg-August University Göttingen, Göttingen 37077, Germany. 9 Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229. 10 Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO 63110; janetkaj@wustl.edu. Item in Clipboard CiteDisplay options Display options Format 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 IC50 (half-maximal inhibitory concentration) of 340 pM against recombinant full-length TMPRSS2 protein, an EC50 (half-maximal effective concentration) of 430 pM in blocking host cell entry into Calu-3 human lung epithelial cells of a newly developed VSV-SARS-CoV-2 chimeric virus, and an EC50 of 74 nM in inhibiting cytopathic effects induced by SARS-CoV-2 virus in Calu-3 cells. Further, MM3122 blocks Middle East respiratory syndrome coronavirus (MERS-CoV) cell entry with an EC50 of 870 pM. MM3122 has excellent metabolic stability, safety, and pharmacokinetics in mice, with a half-life of 8.6 h in plasma and 7.5 h in lung tissue, making it suitable for in vivo efficacy evaluation and a promising drug candidate for COVID-19 treatment. Keywords: COVID-19; PS-SCL; antiviral; protease inhibitor; structure-based drug discovery. Copyright © 2021 the Author(s). Published by PNAS. Conflict of interest statement Competing interest statement: The compounds are covered in two patent application filings from Washington University where J.W.J. and V.C.D. are inventors. J.W.J. and L.K. own company stock in ProteXase Therapeutics, which has licensed the two patent filings. References Mirtaleb M. S., et al. Potential therapeutic agents to COVID-19: An update review on antiviral therapy, immunotherapy, and cell therapy. Biomed. Pharmacother.. 2021;138:111518. McKee D. L., Sternberg A., Stange U., Laufer S., Naujokat C.. Candidate drugs against SARS-CoV-2 and COVID-19. Pharmacol. Res.. 2020;157:104859. Cui W., Yang K., Yang H.. Recent progress in the drug development targeting SARS-CoV-2 main protease as treatment for COVID-19. Front. Mol. Biosci.. 2020;7:616341. Seth S., Batra J., Srinivasan S.. COVID-19: Targeting proteases in viral invasion and host immune response. Front. Mol. Biosci.. 2020;7:215. Luan B., Huynh T., Cheng X., Lan G., Wang H. R.. Targeting proteases for treating COVID-19. J. Proteome Res.. 2020;19:4316–4326. Show all 65 references [x] Cite Copy Format: Send To [x]

参考サイト PubMed: covid-19



バイオクイックニュース日本語版:COVID-19特集

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8月 17, 2020 バイオアソシエイツ

ACE2を提示した細胞外小胞が、侵入するSARS-CoV-2に高効率でデコイとして機能する可能性が報告された

2020年7月8日にオンラインでプレプリントポータルbioRxivに掲載された査読されていないプレプリント論文で、フランスのパリのキュリー研究所の研究者らは、SARS-CoV-2ウイルスのSスパイクタンパク質が結合する表面受容体ACE2(アンギオテンシン変換酵素2)を持つ細胞外小胞( extracellular vesicles )が、侵入するウイルスにデコイとして機能する可能性があることを報告した。 この細胞外小胞は、in vitroでSARS-Co-V2…

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