In animal experiment studies, Chinese researchers have found that a metabolite of the antiviral drug Remdesivir called GS-441524 could help inhibit the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes COVID-19 disease.
Over 46.85 million people worldwide have been infected with the virus, and over 1.2 lives have been lost. To date, no effective antiviral drug is available to treat this infection, and no vaccines are available to block the infection.
Remdesivir, a broad-spectrum antiviral medication developed by the biopharmaceutical company Gilead Sciences, has shown initial success against this viral infection. The drug is approved or authorized for emergency use to treat COVID‑19 in 50 countries.
This new study titled, "Remdesivir Metabolite GS-441524 Efficiently Inhibits SARS-CoV-2 Infection in Mouse Model," was released online as a preprint on the bioRxiv* server, prior to undergoing the peer-review process.
Proposed remdesivir metabolic pathway and chemical structures of metabolites
The pandemic of COVID-19 is currently raging with no effective antiviral drug. In most cases, SARS CoV-2 leads to only mild respiratory symptoms, but in some individuals may lead to acute severe respiratory syndrome (ARDS) and be fatal.
At present, the antiviral drug Remdesivir is the only COVID-19 treatment that has been approved by the United States Food and Drug Administration (FDA). Remdesivir is an RNA-dependent RNA polymerase (RdRP) inhibitor. A recent release of the results of the World Health Organization (WHO) Solidarity Trial has questioned the efficacy of Remdesivir against SARS CoV-2. The trial results questioned its effectiveness in reducing hospital stay and reducing the risk of COVID-19 patients' death.
Pharmacokinetics of Remdesivir
Studies have shown that Remdesivir is metabolized into an active metabolites called the GS-704277, GS-441524 (parent nucleoside), and GS-443902 after it has been administered intravenously. The most important and significant metabolite is GS-441524. GS-441524 has a long half-life of around 27 hours, whereas Remdesivir unchanged has a half-life of around 1 hour in the body. GS-441524 also has a greater bioavailability compared to unchanged Remdesivir. The authors write that the implications of these differences in the pharmacokinetics of unchanged remdesivir and its major metabolite are not clearly understood.
Efficacy of Remdesivir and its metabolite
Studies in the lab have revealed that GS-441524 is less active against the Ebola virus, hepatitis C virus, and respiratory syncytial virus (RSV) compared to unchanged Remdesivir. GS441524 is converted to a monophosphate in the body. This is the most crucial step in the activation of the drug. Remdesivir unchanged bypasses this step and also has a better permeability into the cell. However, studies have shown that GS441524 has a strong efficacy against human coronaviruses (CoV), including SARS CoV 1 and 2, middle east respiratory syndrome coronavirus (MERS-CoV), etc. It is also effective in inhibiting Feline infectious peritonitis (FIP) caused by feline coronaviruses (FCoV) seen in cats. GS-441524, when used in cats with the infection, has shown a 96 percent cure rate, explain the researchers.
Purpose of this study
This study was conducted to compare the efficacy of GS-441524 with Remdesivir against SARS-CoV-2 virus in vitro.
What was done?
Efficacy of Remdesivir and GS-441524 was seen against SARS CoV-2 and Murine hepatitis virus (MHV) on mice models. Pharmacokinetic parameters of the drugs were also tested in animal models and cell cultures. For this study Vero E6 (African green monkey kidney cells), calu-3 (human lung adenocarcinoma cell), and caco-2 cells (colorectal adenocarcinoma) were used. They also used genetically modified mice or AAV-hACE2 transduced mice and those with murine hepatitis virus (MHV).
What was found
Overall results showed that the parent nucleotide of Remdesivir, GS-441524, was capable of inhibition of replication of the SARS-CoV-2 in Vero E6 and other cells. Results of the study were:
- GS-441524 was found to have a good plasma distribution in the animal bodies after administration
- GS-441524 had a long half-life within the mice bodies of nearly 4.8 hours
- GS-441524 was found to have better plasma stability compared to Remdesivir.
- GS-441524 was found to be effective in reducing the viral loads in the affected organs among transduced mice with MHV. The organ toxicities also fell with the use of the drug.
- Authors wrote that these results are "consistent with the previously reported studies that the relative potencies of GS-441524 and remdesivir are cell type dependent".
- GS-441524 did not cause toxicity to the treated cells, and this indicates "its good safety profile," wrote the researchers.
- "GS-441524 treatment was able to significantly inhibit virus replication in the lung by more than 99.9 percent," wrote the researchers.
Conclusions and implications
The study researchers concluded that GS-441524 was the predominant and major metabolite of Remdesivir in the plasma. The effects of Remdesivir against COVID-19 could be partly due to this metabolite. The team wrote that their study showed that GS-441524 could be "a promising and inexpensive drug candidate in the treatment of COVID-19 and future emerging CoVs diseases."
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
- Remdesivir Metabolite GS-441524 Effectively Inhibits SARS-CoV-2 Infection in Mice Models Yingjun Li, Liu Cao, Ge Li, Feng Cong, Yunfeng Li, Jing Sun, Yinzhu Luo, Guijiang Chen, Guanguan Li, Ping Wang, Fan Xing, Yanxi Ji, Jincun Zhao, Yu Zhang, Deyin Guo, Xumu Zhang bioRxiv 2020.10.26.353300; doi: https://doi.org/10.1101/2020.10.26.353300, https://www.biorxiv.org/content/10.1101/2020.10.26.353300v1