The coronavirus 3C-like protease (3CLpro) has a conserved structure and catalytic mechanism and plays a key role during viral polyprotein processing, thus serving as an appealing antiviral drug target. GC376 exerts strong inhibitory effects on the PEDV (porcine epidemic diarrhea virus) 3CLpro with an IC50 of approximately 1.11 μM. The EC50 values of GC376 against CV777 and YN144 (two PEDV strains) were 11.18 and 14.63 μM, respectively implying that GC376 should efficiently inhibit the replication of different PEDV strains. Compared with the non-drug-treated cells, GC376 reduced virus infection at 1.56 μM. It almost completely inhibited virus replication at approximately 6.25 μM, and cell syncytosis disappeared; 12.5 μM GC376 abolished the infection[1].
作用机制
GC376 inhibits PEDV replication by blocking the catalytic residues and binding pocket of 3CLpro[1].
GC376 sodium 细胞实验
Cell Line
Concentration
Treated Time
Description
References
A549 cells
0.0122 to 200 µM
24 hours
Test the cytotoxicity of GC376, CC50 >200 μM
Nat Commun. 2020 Aug 27;11(1):4282.
Fcwf-4 cells
1200 μg/ml
1 hour
To evaluate the virucidal activity of VRE against FIPV, the results showed that the virucidal activity of VRE was limited.
Vet Q. 2024 Dec;44(1):1-13.
BHK-21 cells
50 µM, 75 µM, 100 µM
2 days
Selection of 3CLpro mutations resistant to GC376 and nirmatrelvir
Sci Transl Med. 2023 Jan 11;15(678):eabq7360.
Huh-7ACE2 cells
51 nM (EC50)
24 hours
To test the inhibitory effect of GC376 on SARS-CoV-2 viral replication in Huh-7ACE2 cells, results showed that GC376 exhibited high antiviral potency
Nat Commun. 2022 Apr 7;13(1):1891.
Vero E6 cells
0, 1, 5, 10, 50, 100, 500 µM
24 hours
To evaluate the inhibitory effect of GC376 on SARS-CoV-2, the results showed EC50 values of 0.643 ± 0.085 μM and 0.881 ± 0.109 μM for HRB26 and HRB26M, respectively
Emerg Microbes Infect. 2021 Dec;10(1):481-492.
Vero cells
0.70 µM
48 hours
Evaluate the inhibitory effect of GC376 on SARS-CoV-2 replication, results showed GC376 effectively inhibited virus replication
Nat Commun. 2020 Sep 4;11(1):4417.
Vero E6 cells
0.1 to 100 µM
48 hours
Test the inhibitory effect of GC376 on SARS-CoV-2, EC50 = 0.92 μM
Nat Commun. 2020 Aug 27;11(1):4282.
Vero E6
1.51 µM (EC50)
48 hours
To evaluate the antiviral activity of GC376 against SARS-CoV-2, the results showed an EC50 of 1.51 μM.
J Med Chem. 2022 Feb 24;65(4):2848-2865.
Vero E6
0.068 to 0.086 µM
48 to 72 hours
To evaluate the inhibitory effect of GC376 and its deuterated variants against SARS-CoV-2. The results showed that deuterated variants exhibited stronger antiviral activity than GC376 in Vero E6 cells.
Proc Natl Acad Sci U S A. 2021 Jul 20;118(29):e2101555118.
A549-ACE2
0.069 to 0.10 µM
48 to 72 hours
To evaluate the inhibitory effect of GC376 and its deuterated variants against SARS-CoV-2. The results showed that deuterated variants exhibited stronger antiviral activity than GC376 in A549-ACE2 cells.
Proc Natl Acad Sci U S A. 2021 Jul 20;118(29):e2101555118.
Vero-E6 cells
2.19 ± 0.01 µM (EC50)
72 hours
To evaluate the inhibitory effect of GC376 on SARS-CoV-2 viral replication, results showed that GC376 effectively inhibited viral replication
Nat Commun. 2021 Apr 1;12(1):2016.
Vero-E6 cells
6 µM (EC50)
72 hours
To test the inhibitory effect of GC376 on SARS-CoV-2 viral replication, results showed that GC376 effectively inhibited viral replication
Nat Commun. 2022 Apr 7;13(1):1891.
Vero E6 cells
0.90 µM
To evaluate the antiviral activity of Jun9-62-2R against SARS-CoV-2, showing an EC50 of 0.90 μM.
J Am Chem Soc. 2021 Dec 15;143(49):20697-20709.
Caco2-hACE2 cells
2.05 µM
To evaluate the antiviral activity of Jun9-62-2R against SARS-CoV-2, showing an EC50 of 2.05 μM.
J Am Chem Soc. 2021 Dec 15;143(49):20697-20709.
Vero E6 cells
0.18 µM
To test the inhibitory ability of GC376 against SARS-CoV-2 infection, the results showed that GC376 has significant inhibitory effects.
Acta Pharmacol Sin. 2023 Jan;44(1):255-257.
GC376 sodium 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
K18-hACE2 mice
Intraperitoneal injection
100 mg/kg/day or 125 mg/kg/day
Once daily for 10 days
To evaluate the efficacy of deuterated GC376 variants in a lethal SARS-CoV-2 infection mouse model. The results showed that treatment significantly improved survival rates and reduced viral load and pathological changes in the lungs.
Proc Natl Acad Sci U S A. 2021 Jul 20;118(29):e2101555118.
BALB/c mice
SARS-CoV-2 infection model
Intramuscular injection
40 or 8 mM/l, 100 µl
Daily for 15 days
To evaluate the in vivo antiviral efficacy of GC376 against SARS-CoV-2, the results showed that high-dose GC376 significantly reduced viral replication in the lungs but failed to completely block viral proliferation
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