Ensitrelvir (S-217622) represents the first orally administered non-covalent, non-peptidic inhibitor of the SARS-CoV-2 3CL protease, with an IC50 of 13 nM[1][2].
体内研究
Ensitrelvir inhibits the replication of SARS-CoV-2 within the lungs of mice in a dose-dependent manner[2].
体外研究
In a cytopathic effect (CPE) inhibition assay involving SARS-CoV-2 infected VeroE6/TMPRSS2 cells, Ensitrelvir displays EC50 values around 0.4 μM for both the wild-type virus and the Alpha, Beta, Gamma, and Delta variants. EC50 values for SARS-CoV and MERS-CoV are 0.21 μM and 1.4 μM, respectively[1].
Ensitrelvir 细胞实验
Cell Line
Concentration
Treated Time
Description
References
VeroE6/TMPRSS2 cells
20 μM
8, 16, 24, 32, 40, 48, 56, 72, and 96 h
To evaluate the growth of Nsp5-M49L, Nsp5-E166A, and Nsp5-M49L/E166A in vitro with or without ensitrelvir. Results showed that wild-type virus replicated efficiently in VeroE6/TMPRSS2 cells, while 20 μM ensitrelvir completely inhibited wild-type virus replication. Nsp5-M49L and Nsp5-E166A showed slightly delayed growth in the absence of ensitrelvir, while Nsp5-M49L/E166A showed moderate growth delay. In the presence of ensitrelvir, propagation of Nsp5-M49L was severely impaired, Nsp5-E166A propagation was not detected at all, whereas growth of Nsp5-M49L/E166A was less affected.
Nat Commun. 2023 Jul 15;14(1):4231
BHK-21 cells
30-100 μM
48-72 hours
To select SARS-CoV-2 3CLpro mutations conferring resistance to Ensitrelvir, identifying 39 unique mutations including Y54C, L167F, Q192R, etc.
Sci Transl Med. 2023 Jan 11;15(678):eabq7360
Primary human bronchial epithelial cells (HBE cells)
12, 37, 111, 333 nM
72 hours
progeny virus titers were under the detection limit at 333 nM or more
Evaluated anti-SARS-CoV-2 activity with EC50 of 0.20 µM
Nat Commun. 2023 Feb 25;14(1):1076
VeroE6 cells
0.11 µM
Evaluated anti-SARS-CoV-2 activity with EC50 of 0.11 µM
Nat Commun. 2023 Feb 25;14(1):1076
Calu-3 cells
0.078 μM
Evaluated anti-SARS-CoV-2 activity, showing EC50=0.078 μM with no cytotoxicity (CC50>100 μM)
Adv Sci (Weinh). 2024 Nov;11(43):e2404884
Ensitrelvir 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Syrian hamsters
COVID-19 hamster model
Oral gavage
60 mg/kg per 12 h (120 mg/kg/day)
Twice daily for 3 days
To evaluate the therapeutic efficacy of S-217622 against BA.2 variants, results showed that S-217622 significantly reduced viral titers in both the upper and lower respiratory tracts of hamsters.
Nature. 2022 Jul;607(7917):119-127
Syrian hamsters
SARS-CoV-2 Delta variant infection model
Oral
30 mg/kg and 200 mg/kg
Twice a day from 0 hpi to 4 dpi
Decreases viral load and ameliorates disease severity
Sci Transl Med. 2023 Jan 18;15(679):eabq4064
Syrian hamsters
SARS-CoV-2 infected hamster model
Oral
200 mg/kg
Twice daily for 5 days
Evaluated the therapeutic effect of Ensitrelvir in a delayed dosing model, showing that combination therapy improved respiratory conditions and reduced pneumonia development.
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