Remdesivir- Mechanism of Action, Uses, Synthesis & COVID-19

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Last Updated on November 24, 2020 by Sagar Aryal

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Update: WHO says, “There is currently no evidence that Remdesivir improves survival or the need for ventilation,”

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.
  • Current research trials of the drug on COVID-19 has revealed that it is effective against certain key enzymes of SARS-CoV-2, that caused COVID-19.
  • According to a research paper published on the 13th April 2020 on the Science Daily, by the University of Alberta Faculty of Medicine & Dentistry, scientists have shown that Remdesivir is highly effective in stopping the replication mechanism of the coronavirus that causes COVID-19.
  • The finding follows closely on research demonstrating how the drug worked against the Middle East Respiratory Syndrome (MERS) virus, a related coronavirus.

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 as 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 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. COVID-19

  • Gilead began laboratory testing for the treatment of COVID-19 using Remdesivir in January 2020, since it had shown to be active against SARS and MERS using animal models.
  • On 21 January 2020, the Wuhan Institute of Virology applied for a Chinese USE PATENT on Remdesivir for the novel use of treating COVID-19.
  • Late January, Remdesivir was used on a US patient who had confirmed to have SARS-CoV-2 in Washington for çompassionate use’ after he progressed to pneumonia. The patient’s condition improved and he was discharged however it could not be confirmed that the drug typically cured the patient.
  •  During the same period, the Chinese medical researchers reported that Remdesivir seemed to have “fairly good inhibitory effects” on SARS-CoV-2, after which requests to begin clinical testing were submitted. On 6 February 2020, a clinical trial of Remdesivir began in China.
  • On 17 March 2020, the drug was provisionally approved for use for COVID-19 patients in critical condition in the Czech Republic and on 18th, March 2020, the WHO launched a four-arm clinical trial, known as RECOVERY trial, the largest globally for trials of different drugs on groups of patients including Remdesivir.
  • On 20 March 2020, the Cleveland, Ohio-based University Hospitals stated they would run two clinical trials to test the effectiveness of Remdesivir against COVID-19.
  • Early results from Phase III trials in Chicago indicate that Remdesivir may be beneficial. Clinical improvement was observed in 36 of 53 patients treated with compassionate-use Remdesivir.

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:

  1. Preparation of an intermediate a from L-alanine and phenyl phosphorodichloridate in presence of triethylamine and dichloromethane.
  2. Oxidation of triple benzyl-protected ribose by dimethyl sulfoxide with acetic anhydride to produce the lactone intermediate b
  3. Pyrrolo[2,1-f][1,2,4]triazin-4-amine is brominated and protected by excess trimethylsilyl chloride.
  4. n-Butyllithium undergoes a halogen-lithium exchange reaction with the bromide at −78 °C (−108 °F) to yield the intermediate c.
  5. 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.
  6. 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.
  7. 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.
  8. The isomers were then separated via reversed-phase High-Performance Liquid Chromatography (HPLC).
  9. The optically pure compound and intermediate a are reacted with trimethyl phosphate and methylimidazole to obtain a diastereomer mixture of Remdesivir.
  10. Using the chiral resolution method, optically active drug, Remdesivir in its pure form is obtained.

References

  1. https://www.gilead.com/purpose/advancing-global-health/covid-19/remdesivir-clinical-trials
  2. https://www.statnews.com/2020/04/16/early-peek-at-data-on-gilead-coronavirus-drug-suggests-patients-are-responding-to-treatment/
  3. 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
  4. https://www.reuters.com/article/us-health-coronavirus-gilead-sciences/report-says-covid-19-patients-respond-to-gileads-remdesivir-shares-surge-idUSKBN21Y3GV
  5. https://www.biopharmadive.com/news/coronavirus-remdesivir-gilead-antiviral-drug-covid-19/573261/
  6. https://en.wikipedia.org/wiki/Remdesivir
  7. https://www.jbc.org/content/early/2020/04/13/jbc.RA120.013679.abstract

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  • 1% – https://theweek.com/speedreads/909328/report-covid19-patients-are-responding-quickly-experimental-drug-remdesivir
  • <1% – https://www.sciencedirect.com/science/article/pii/S0924857920300984
  • <1% – https://www.researchgate.net/publication/332217091_Mechanism_of_Inhibition_of_Ebola_Virus_RNA-Dependent_RNA_Polymerase_by_Remdesivir
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4 thoughts on “Remdesivir- Mechanism of Action, Uses, Synthesis & COVID-19”

  1. hi, we are writing a review article on remdesivir and we think the picture that is used here to explain the action of remdesivir is appropriate for our article, it would be very helpful if you permit us to use that diagram. We will use that as a reference with all due credits. thanks

    Reply
  2. Hi,
    Thank you for putting all the information together here.
    I believe you have a couple of errors in your textual description of remdesivir. The image clearly shows that GS-421544 is the active form of the drug. The image also shows that THIS is the form that actually binds RNA-dependent RNA polymerase, which would make this form of drug the active form. Therefore, please, correct this bullet point:
    “These mechanisms are linked to Remdesivir’s ability to metabolize into an inactive form known as GS-441524 which is an adenosine nucleotide analog.”

    It should say: “”These mechanisms are linked to Remdesivir’s ability to metabolize into an active form known as GS-441524 which is an adenosine nucleotide analog.”

    Also, the bullet point below is inaccurate. You say:
    “Remdesivir resembling as an RNA building block becomes the new RNA strand.” This is not good. Instead, it should say something like “Remdesivir resembling as an RNA building block becomes a part of the new RNA strand.” RNA strands are made of multiple nucleotides; one nucleotide does not make it a strand.
    Thank you in advance for correcting these.

    Reply

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