tetano
Editor, Senior Moderator
J Virol
. 2021 Jun 23;JVI0086121.
doi: 10.1128/JVI.00861-21. Online ahead of print.
Structural basis of covalent inhibitory mechanism of TMPRSS2-related serine proteases by camostat
Gaohui Sun[SUP] 1 [/SUP], Yaqun Sui[SUP] 1 [/SUP], Yang Zhou[SUP] 1 [/SUP], Junlin Ya[SUP] 1 [/SUP], Cai Yuan[SUP] 2 [/SUP], Longguang Jiang[SUP] 1 3 [/SUP], Mingdong Huang[SUP] 1 [/SUP]
Affiliations
Abstract
SARS-CoV-2 is the viral pathogen causing the COVID19 global pandemic. No effective treatment for COVID-19 has been established yet. TMPRSS2 is essential for viral spread and pathogenicity by facilitating the entry of SARS-CoV-2 onto host cells. The protease inhibitor camostat, an anticoagulant used in the clinic, has potential anti-inflammatory and anti-viral activities against COVID-19. However, the potential mechanisms of viral resistance and antiviral activity of camostat are unclear. Herein, we demonstrate high inhibitory potencies of camostat for a panel of serine proteases, indicating the camostat is a broad-spectrum inhibitor of serine proteases. In addition, we determined the crystal structure of camostat in complex with a serine protease (uPA), which reveals that camostat insert to the S1 pocket of uPA but was hydrolyzed by uPA, and the cleaved camostat covalently binds to the Ser195. We also generated the homology model of the structure of the TMPRSS2 serine protease domain. The model showed that camostat used the same inhibitory mechanism to inhibit the activity of TMPRSS2, and subsequently preventing SARS-CoV-2 spread. Importance section Serine proteases are a large family of enzymes critical for multiple physiological processes and proven diagnostic and therapeutic targets in several clinical indications. A serine protease transmembrane protease serine 2 (TMPRSS2) was recently found to mediate SARS-coronavirus 2 (SARS-CoV-2) entry into the host. camostat mesylate (FOY 305), a serine protease inhibitor active against TMPRSS2 and used for the treatment of oral squamous cell carcinoma and chronic pancreatitis, inhibits SARS-CoV-2 infection of human lung cells. However, the direct inhibition mechanism of camostat mesylate for TMPRSS2 is unclear. Herein, we demonstrate camostat used the same inhibitory mechanism to inhibit the activity of TMPRSS2 as uPA, and subsequently preventing SARS-CoV-2 spread.
. 2021 Jun 23;JVI0086121.
doi: 10.1128/JVI.00861-21. Online ahead of print.
Structural basis of covalent inhibitory mechanism of TMPRSS2-related serine proteases by camostat
Gaohui Sun[SUP] 1 [/SUP], Yaqun Sui[SUP] 1 [/SUP], Yang Zhou[SUP] 1 [/SUP], Junlin Ya[SUP] 1 [/SUP], Cai Yuan[SUP] 2 [/SUP], Longguang Jiang[SUP] 1 3 [/SUP], Mingdong Huang[SUP] 1 [/SUP]
Affiliations
- PMID: 34160253
- DOI: 10.1128/JVI.00861-21
Abstract
SARS-CoV-2 is the viral pathogen causing the COVID19 global pandemic. No effective treatment for COVID-19 has been established yet. TMPRSS2 is essential for viral spread and pathogenicity by facilitating the entry of SARS-CoV-2 onto host cells. The protease inhibitor camostat, an anticoagulant used in the clinic, has potential anti-inflammatory and anti-viral activities against COVID-19. However, the potential mechanisms of viral resistance and antiviral activity of camostat are unclear. Herein, we demonstrate high inhibitory potencies of camostat for a panel of serine proteases, indicating the camostat is a broad-spectrum inhibitor of serine proteases. In addition, we determined the crystal structure of camostat in complex with a serine protease (uPA), which reveals that camostat insert to the S1 pocket of uPA but was hydrolyzed by uPA, and the cleaved camostat covalently binds to the Ser195. We also generated the homology model of the structure of the TMPRSS2 serine protease domain. The model showed that camostat used the same inhibitory mechanism to inhibit the activity of TMPRSS2, and subsequently preventing SARS-CoV-2 spread. Importance section Serine proteases are a large family of enzymes critical for multiple physiological processes and proven diagnostic and therapeutic targets in several clinical indications. A serine protease transmembrane protease serine 2 (TMPRSS2) was recently found to mediate SARS-coronavirus 2 (SARS-CoV-2) entry into the host. camostat mesylate (FOY 305), a serine protease inhibitor active against TMPRSS2 and used for the treatment of oral squamous cell carcinoma and chronic pancreatitis, inhibits SARS-CoV-2 infection of human lung cells. However, the direct inhibition mechanism of camostat mesylate for TMPRSS2 is unclear. Herein, we demonstrate camostat used the same inhibitory mechanism to inhibit the activity of TMPRSS2 as uPA, and subsequently preventing SARS-CoV-2 spread.