GS-5734 is a monophosphoramidate prodrug of an adenosine analog that exhibits antiviral activity against a wide range of filoviruses including Marburg virus and multiple variants of Ebola virus. It inhibited replication of Ebola virus in several human cell types including primary macrophages, Hela cells, and human endothelial cells with EC50 values of 0.06 to 0.14μM. In liver Huh-7 cells infected with the Makona variant of Ebola virus, treatment with GS-5734 resulted in a dose-dependent reduction in viral RNA production and the amount of infectious viruses. GS-5734 exhibited a short plasma half-life (t1/2 = 0.39h) in rhesus monkeys administrated with a 10mg/kg dose via intravenous injection. It also rapidly distributed into peripheral blood mononuclear cells and converted to nucleoside triphosphates within 2h of dose administration. In rhesus monkeys intramuscularly inoculated with Ebola virus, treatment with 3mg/kg GS-5734 beginning on day 0 or day 2 conferred an antiviral effect and improved survival (33% in the day 0 group and 66% in the day 2 group) relative to vehicle-treated animals. Animals in which GS-5734 was administered at a loading dose of 10mg/kg followed by once-daily 3mg/kg doses beginning either 2 days or 3 days after virus exposure survived to the end of the in-life phase. Rhesus monkeys treated with 10mg/kg doses of GS-5734 beginning 3 days following virus exposure also survived to 28 days following virus exposure. This group also showed ameliorated Ebola virus disease-related clinical disease signs and markers of coagulopathy and end-organ pathophysiology compared to other GS-5734-treated monkeys.[1]
作用机制
GS-5734 is a potent and selective inhibitor of Ebola virus. It inhibits replication of Ebola virus by targeting its RNA-dependent RNA-polymerases and inhibiting viral RNA synthesis following efficient intracellular conversion to active nucleoside triphosphates. [1]
Remdesivir/瑞德西韦 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HAE cells
0.074 µM (EC50)
48-72 hours
Evaluate the inhibitory effect of GS-5734 on SARS-CoV and MERS-CoV, results showed GS-5734 significantly reduced viral titer
mBio. 2018 Mar 6;9(2):e00221-18
human induced pluripotent stem cell (iPS)-derived cardiomyocytes
1 μM
72 h
To evaluate the effect of Remdesivir on cardiomyocyte electrophysiology, results showed that Remdesivir significantly prolonged the action potential duration (APD90), and this prolongation was markedly attenuated by the UTS2R antagonist.
Commun Biol. 2023 May 12;6(1):511.
neonatal rat cardiomyocytes (NRCMs)
1 μM
48 h
To evaluate the effect of Remdesivir on cardiomyocyte contractility, results showed that Remdesivir significantly reduced cardiomyocyte contractility, and this effect was significantly attenuated by the UTS2R antagonist.
Commun Biol. 2023 May 12;6(1):511.
Vero E6 cells
133.2 μM
72 h
To evaluate the antiviral activity of Remdesivir against SARS-CoV-2, the results showed that the IC50 value of Remdesivir was 1.42 μM, and the selectivity index (SI) was 94.00.
Phytomedicine. 2022 Jan;95:153874.
Vero E6 cells
10 µM
30 h
To evaluate the antiviral activity of Remdesivir against SARS-CoV-2, results showed that at 10 µM concentration, Remdesivir protected more than 99% of cells from virus-induced cytopathic effects (CPE).
Front Microbiol. 2022 May 10;13:877813.
NIH-3T3 cells
12.5, 25, 50 μM
24 h
To evaluate the effect of Remdesivir on TGF-β1-induced proliferation and migration of lung fibroblasts. Results showed that Remdesivir dose-dependently inhibited the proliferation and migration of TGF-β1-activated fibroblasts.
Front Pharmacol. 2021 Aug 26;12:692346.
A549 cells
12.5, 25, 50 μM
24 h
To evaluate the effect of Remdesivir on TGF-β1-induced phenotypic transition in alveolar epithelial cells. Results showed that Remdesivir significantly increased the expression of the epithelial marker E-cadherin and decreased the expression of the mesenchymal markers N-cadherin and vimentin.
Front Pharmacol. 2021 Aug 26;12:692346.
Vero cells
10 µM
24 h
Evaluate the inhibitory effect of Remdesivir on SARS-CoV-2 replication, results showed significant inhibition at 10 µM concentration
Cell Chem Biol. 2022 May 19;29(5):774-784.e8.
A549ACE2+ cells
10 µM
24 h
Evaluate the inhibitory effect of Remdesivir on SARS-CoV-2 replication, results showed significant inhibition at 10 µM concentration
Cell Chem Biol. 2022 May 19;29(5):774-784.e8.
VeroE6 cells
0.74 µM
2 days
Evaluate the in vitro antiviral activity of Remdesivir against SARS-CoV-2, showing an EC50 of 0.74 µM.
EMBO Rep. 2022 May 4;23(5):e53820.
A549ACE2+ cells
10 µM
24 h
To evaluate the inhibitory effect of Remdesivir on SARS-CoV-2 infection. The results showed that Remdesivir at 10 μM concentration can significantly inhibit viral replication, but its effect is less significant compared to Acriflavine (ACF)
Cell Chem Biol. 2022 May 19;29(5):774-784.e8.
Vero cells
10 µM
24 h
To evaluate the inhibitory effect of Remdesivir on SARS-CoV-2 infection. The results showed that Remdesivir at 10 μM concentration can significantly inhibit viral replication, but its effect is less significant compared to Acriflavine (ACF)
Cell Chem Biol. 2022 May 19;29(5):774-784.e8.
Remdesivir/瑞德西韦 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
HACE2 transgenic C57BL/6 mice
SARS-CoV-2 infection model
Oral
50 mg/kg
Once daily for 5 days
To evaluate the antiviral and anti-inflammatory effects of Remdesivir in SARS-CoV-2 infected mice, the results showed that Remdesivir significantly reduced the mortality of mice and decreased lung virus titers.
Phytomedicine. 2022 Jan;95:153874.
BALB/c mice
Normal mice
Intravenous injection, Transtracheal injection
20 mg/kg
Single dose
To evaluate the pharmacokinetics and tissue distribution of NTP in the lung under different administration routes. The results showed that the NTP concentration and accumulation in the Rdv-lips transtracheal injection group were significantly higher than those in the Rdv-cyc intravenous injection group, and the NTP conversion rate of Rdv-lips was faster.
Asian J Pharm Sci. 2021 Nov;16(6):772-783.
C57BL/6 mice
Bleomycin-induced pulmonary fibrosis model
Intraperitoneal injection
10 mg/kg, 20 mg/kg
Once daily for 14 days
To evaluate the preventive effect of Remdesivir on bleomycin-induced pulmonary fibrosis. Results showed that Remdesivir significantly alleviated bleomycin-induced collagen deposition and improved pulmonary function.
Front Pharmacol. 2021 Aug 26;12:692346.
K18-ACE2 mice
SARS-CoV-2 infection model
Intramuscular
25 mg/kg
Once daily for 6 days
Evaluate the inhibitory effect of Remdesivir on SARS-CoV-2 replication in vivo, results showed significant reduction of viral replication in the brain and lungs
Cell Chem Biol. 2022 May 19;29(5):774-784.e8.
K18-ACE2 mice
SARS-CoV-2 infection model
Oral and intramuscular
100 mg/kg (oral), 5 mg/kg or 15 mg/kg (intramuscular)
Once daily (oral), twice daily (intramuscular), for 6 days
To evaluate the inhibitory effect of ACF on SARS-CoV-2 replication in vivo, the results showed that both oral and intramuscular administration of ACF significantly reduced viral replication in the brain and lungs.
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