tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A
. 2021 Oct 26;118(43):e2108728118.
doi: 10.1073/pnas.2108728118.
A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells
Matthew Mahoney[SUP] 1 2 [/SUP], Vishnu C Damalanka[SUP] 1 [/SUP], Michael A Tartell[SUP] 3 4 [/SUP], Dong Hee Chung[SUP] 5 [/SUP], André Luiz Lourenço[SUP] 5 [/SUP], Dustin Pwee[SUP] 6 [/SUP], Anne E Mayer Bridwell[SUP] 3 [/SUP], Markus Hoffmann[SUP] 7 8 [/SUP], Jorine Voss[SUP] 1 [/SUP], Partha Karmakar[SUP] 1 [/SUP], Nurit P Azouz[SUP] 9 [/SUP], Andrea M Klingler[SUP] 9 [/SUP], Paul W Rothlauf[SUP] 3 4 [/SUP], Cassandra E Thompson[SUP] 3 [/SUP], Melody Lee[SUP] 5 [/SUP], Lidija Klampfer[SUP] 2 [/SUP], Christina L Stallings[SUP] 3 [/SUP], Marc E Rothenberg[SUP] 9 [/SUP], Stefan Pöhlmann[SUP] 7 8 [/SUP], Sean P J Whelan[SUP] 3 [/SUP], Anthony J O'Donoghue[SUP] 6 [/SUP], Charles S Craik[SUP] 5 [/SUP], James W Janetka[SUP] 10 2 [/SUP]
Affiliations
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[SUB]50[/SUB] (half-maximal inhibitory concentration) of 340 pM against recombinant full-length TMPRSS2 protein, an EC[SUB]50[/SUB] (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 EC[SUB]50[/SUB] 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 EC[SUB]50[/SUB] 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.
. 2021 Oct 26;118(43):e2108728118.
doi: 10.1073/pnas.2108728118.
A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells
Matthew Mahoney[SUP] 1 2 [/SUP], Vishnu C Damalanka[SUP] 1 [/SUP], Michael A Tartell[SUP] 3 4 [/SUP], Dong Hee Chung[SUP] 5 [/SUP], André Luiz Lourenço[SUP] 5 [/SUP], Dustin Pwee[SUP] 6 [/SUP], Anne E Mayer Bridwell[SUP] 3 [/SUP], Markus Hoffmann[SUP] 7 8 [/SUP], Jorine Voss[SUP] 1 [/SUP], Partha Karmakar[SUP] 1 [/SUP], Nurit P Azouz[SUP] 9 [/SUP], Andrea M Klingler[SUP] 9 [/SUP], Paul W Rothlauf[SUP] 3 4 [/SUP], Cassandra E Thompson[SUP] 3 [/SUP], Melody Lee[SUP] 5 [/SUP], Lidija Klampfer[SUP] 2 [/SUP], Christina L Stallings[SUP] 3 [/SUP], Marc E Rothenberg[SUP] 9 [/SUP], Stefan Pöhlmann[SUP] 7 8 [/SUP], Sean P J Whelan[SUP] 3 [/SUP], Anthony J O'Donoghue[SUP] 6 [/SUP], Charles S Craik[SUP] 5 [/SUP], James W Janetka[SUP] 10 2 [/SUP]
Affiliations
- PMID: 34635581
- DOI: 10.1073/pnas.2108728118
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[SUB]50[/SUB] (half-maximal inhibitory concentration) of 340 pM against recombinant full-length TMPRSS2 protein, an EC[SUB]50[/SUB] (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 EC[SUB]50[/SUB] 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 EC[SUB]50[/SUB] 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.