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What is Remdesivir?
- Remdesivir is an antiviral drug that was developed by Gilead Sciences in 2014 as a possible treatment for Ebola Hemorrhagic Virus (EBV) and Marburg Virus infection.
- It is a nucleotide analog, specifically an adenosine analog, evidenced to have broad-spectrum activity against the single-stranded RNA viruses.
- Research with the Ebola virus indicated that Remdesivir had very low efficacy against the virus because it causes mutations in the Rhesus Monkey hepatitis virus RNA replicase which causes partial resistance to the virus.
- These mutations make the viruses less effective in nature, and the researchers believe they will likely not persist where the drug is not being used.
Mechanism of Action of Remdesivir
- Research by scientists at Götte’s lab found that the use of polymerase enzyme extracted from coronavirus, MERS noting that the enzymes can incorporate Remdesivir into the synthesizing single-stranded RNA.
- Remdesivir resembling an RNA building block becomes a part of the new RNA strand.
- It was noted that after adding Remdesivir, the polymerase enzyme stops adding more RNA subunits, stopping genome replication.
- These mechanisms are linked to Remdesivir’s ability to metabolize into an active form known as GS-441524 which is an adenosine nucleotide analog.
- The GS-441524 interferes with the action of viral RNA-dependent RNA polymerase and evades proofreading by viral exoribonuclease (ExoN). This decreases viral RNA production.
- Studies are still ongoing to understand whether the prodrug terminates RNA chains or it causes mutations in the RNA.
- Using Ebola virus studies, it was noted that the prodrug, Remdesivir, inhibited the action of RNA-dependent RNA polymerase, causing the elongation of the synthesized chain.
Uses of Remdesivir
1. Ebola virus
- Remdesivir is the drug that was initially designed for the treatment of the Ebola Hemorrhagic Virus (EBV) started clinical trials in 2014-2016 during the West African Ebola Virus epidemic on people who had the disease.
- The trials were under the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) and Gilead Sciences.
- The initial results were very promising until August 2019 where the monoclonal antibody (mAb114 and REGN-EB3) treatment was found to be more effective than Remdesivir.
- However, the drug had established its safety profile during the trials.
2. Remdesivir and COVID-19
Figure: Remdesivir- Potential Repurposed Drug Candidate for COVID-19. Image created with biorender.com
3. Use for other animals
- In 2019, Remdesivir showed promise for the treatment of coronavirus infection in cats known as feline infectious peritonitis.
- However, it has not been approved for treating the Feline coronavirus by the FDA but it has been available in unregulated black markets since 2019.
Synthesis of Remdesivir
The synthesis of Remdesivir was done sequentially in multiple steps as follows:
- Preparation of an intermediate a from L-alanine and phenyl phosphorodichloridate in presence of triethylamine and dichloromethane.
- Oxidation of triple benzyl-protected ribose by dimethyl sulfoxide with acetic anhydride to produce the lactone intermediate b
- Pyrrolo[2,1-f][1,2,4]triazin-4-amine is brominated and protected by excess trimethylsilyl chloride.
- n-Butyllithium undergoes a halogen-lithium exchange reaction with the bromide at −78 °C (−108 °F) to yield the intermediate c.
- Drop by drop, add the intermediate b to a solution that contains the intermediate c, and put out the reaction in a weakly acidic aqueous solution to obtain a mixture of 1: 1 anomer.
- It was then reacted with an excess of trimethylsilyl cyanide in dichloromethane at −78 °C (−108 °F) for 10 minutes. Trimethylsilyl triflate was added and reacted for an hour, and the mixture was quenched in an aqueous sodium hydrogen carbonate to obtain a nitrile intermediate.
- The protective group, benzyl, was then removed with boron trichloride in dichloromethane at −20 °C (−4 °F). The excess of boron trichloride was quenched in a mixture of potassium carbonate and methanol obtaining a benzyl-free intermediate.
- The isomers were then separated via reversed-phase High-Performance Liquid Chromatography (HPLC).
- The optically pure compound and intermediate a are reacted with trimethyl phosphate and methylimidazole to obtain a diastereomer mixture of Remdesivir.
- Using the chiral resolution method, optically active drug, Remdesivir in its pure form is obtained.
- Wang, M., Cao, R., Zhang, L. et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 30, 269–271 (2020). https://doi.org/10.1038/s41422-020-0282-0
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