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.
The electrocatalytic applications of traditional polyimide film and carbon nanomaterials are hindered due to a shortage of three-dimensional hierarchical conductivity and porous structure. Herein, a novel polyimide-based electrode based on a highly efficient palladium nanocatalyst embellished three-dimensional reduced graphene oxide/polyimide foam (Pd/3D RGO@PI foam, signed PRP) toward H 2 O 2 electroreduction was designed and prepared through thermal foaming procedure, followed by facile dip-drying method and electrodeposition. As expected, such a binder-free, 3D hierarchical structure PRP electrode presented high catalytic property, good stability, as well as low activation energy toward H 2 O 2 electroreduction during the electrochemical measurement period. The PRP electrode showed a reduction current density of 810 mA•cm −2 at −0.2 V (vs Ag/AgCl) in 2.0 mol•L −1 H 2 SO 4 and 2.0 mol•L −1 H 2 O 2 . Moreover, the PRP electrode also illustrated good reproducibility and repeatability. Reproducibility presented almost 95.8% of the initial current density after 1000 cycles test. Also, the activation energy of H 2 O 2 electroreduction on 3D PRP electrode was 21.624 kJ•mol −1 . Benefiting from the 3D hierarchical structure and efficient catalyst, the PRP electrode exhibited excellent electrocatalytic performance and was considered to be a potential candidate material for fuel cells.
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