Microbe / Health News

REMDESIVIR – THE ‘PROBABLE’ COVID-19 GAME CHANGER

Written by MicroDok

Remdesivir is a nucleotide analogue ‘antiviral’ prodrug. It inhibits viral RNA polymerases, thereby stopping continual viral replication in infected individuals. Recent studies have shown that remdesivir possess in vitro antiviral activity against SARS-CoV-2, the causative agent of the dreaded COVID-19 pandemic that is currently ravaging the economy of the entire world.

Remdesivir which can also called GS-5734 compound, is an adenosine triphosphate analog that was first described in the medical literature in 2016 as a potential treatment for Ebola and Marburg virus disease. But In 2017, the antiviral activity of remdesivir against viruses in the Coronaviridae (coronavirus) family was also demonstrated. Currently, remdesivir is being researched as a potential treatment to SARS-CoV-2. SARS-CoV-2 is the coronavirus strain that is responsible for COVID-19.

Remdesivir is a broad-spectrum antiviral medication developed by the biopharmaceutical company Gilead Sciences. As of 2020, remdesivir is being tested as a specific treatment for COVID-19, and has been issued an Emergency Use Authorization (EUA) in the U.S. for those hospitalized with severe (COVID-19) disease.

As aforementioned, remdesivir was originally created as a general antiviral and was later tested in Ebola patients, though it did not perform well in a landmark trial.

Fig 1. Chemical structure of GS-5734 compound (remdesivir)

Molecular formular of GS-5734: C27H35N6O8P

IUPAC name OF GS-5734 compound:

2-ethylbutyl (2S)-2-[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxyoxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate

Remdesivir is intracellularly metabolized to an analogue of adenosine triphosphate that inhibits viral RNA polymerases. Remdesivir has broad-spectrum activity against members of several virus families, including filoviruses (e.g., Ebola) and coronaviruses (e.g., SARS-CoV and Middle East respiratory syndrome coronavirus [MERS-CoV]). In terms of its antiviral efficacy, remdesivir has shown prophylactic and therapeutic efficacy in nonclinical models of these coronaviruses.

SIDE EFFECTS OF REMDESIVIR

Since all drugs are potential poisons and rarely without some untoward effects on the end users including humans, remdesivir have some side effects. The most common adverse effects in studies of remdesivir for COVID‑19 include respiratory failure and blood biomarkers of organ impairment, including low albumin, low potassium, low count of red blood cells, low count of platelets that help with clotting, and yellow discoloration of the skin. Other reported side effects include gastrointestinal distress, elevated transaminase levels in the blood (liver enzymes), and infusion site reactions. Other possible side effects of remdesivir include:

  • Infusionrelated reactions: Signs and symptoms of infusion‐related reactions may include: low blood pressure, nausea, vomiting, sweating, and shivering.
  • Increases in levels of liver enzymes, seen in abnormal liver blood tests: Increases in levels of liver enzymes have been seen in people who have received remdesivir, which may be a sign of inflammation or damage to cells in the liver.

MECHANISM OF ACTION OF REMDESIVIR             

Remdesivir is an adenosine triphosphate analog. As an adenosine nucleotide triphosphate analog, the active metabolite of remdesivir interferes with the action of viral RNA-dependent RNA polymerase and evades proofreading by viral exoribonuclease (ExoN), causing a decrease in viral RNA production. In some viruses such as the respiratory syncytial virus it causes the RNA-dependent RNA polymerases to pause, but its predominant effect (as in Ebola) is to induce an irreversible chain termination. Unlike with many other chain terminators, this is not mediated by preventing addition of the immediately subsequent nucleotide, but is instead delayed, occurring after five additional bases have been added to the growing RNA chain. Hence remdesivir is classified as a delayed chain terminator. Generally, remdesivir helps to inhibit viral replication in vivo, thereby limiting the possible spread and pathogenic effect of the invading virus in the patient. According to the US NIAID, remdesivir helps to reduce the recovery time of COVID-19 patients.

HOW IT ALL STARTED

As of April 2020, remdesivir was viewed as the most promising treatment for COVID-19, and was included among four treatments under evaluation in the international Solidarity trial and European Discovery trial in the race for the discovery of a possible ‘functional’ treatment for COVID-19. The US FDA (Food and Drug Administration) stated on 1 May 2020 that it is “reasonable to believe” that known and potential benefits of remdesivir outweigh its known and potential risks, in some specific populations hospitalized with severe COVID‑19.

On 29 April 2020, the National Institute of Allergy and Infectious Diseases (NIAID) announced that remdesivir was better than a placebo in reducing time to recovery for people hospitalized with advanced COVID‑19 and lung involvement. Previously data from one randomized controlled trial was released early in error and before peer review; it did not show improvement. Gilead Sciences stated that due to low enrollment the study was halted while a non-associated researcher stated it does mean if there is any benefit, then that benefit will be small.

In January 2020, Gilead began laboratory testing of remdesivir against SARS-CoV-2, stating that remdesivir had been shown to be active against severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) in animal models. On 21 January 2020, the Wuhan Institute of Virology applied for a Chinese “use patent”, for treating COVID‑19.

In a trial in China over February-March 2020, remdesivir was not effective in reducing the time for improvement from COVID‑19 or deaths, and caused various adverse effects, requiring the investigators to terminate the trial.

But in March 2020, a small trial of remdesivir in rhesus macaque monkeys with COVID‑19 infections found that it prevents disease progression. On 18 March 2020, the World Health Organization (WHO) announced the launch of a trial that would include one group treated with remdesivir. Other clinical trials are currently underway or planned.

Early data from a controlled trial carried out by the US-based National Institutes of Health, suggests that remdesivir is effective in reducing the recovery time from 15 to 11 days in people seriously ill with COVID‑19. This data contradicted findings from an earlier trial carried out in China that showed remdesivir was not effective in treating COVID-19. In April 2020, the European Medicines Agency (EMA) started a ‘rolling review’ of data on the use of remdesivir in COVID‑19.

REFERENCES    

Cao B, Wang C, Wang Y, Zhou F, Zhang D, Zhao J, Du R, Hu Y, Cheng Z, Gao L, Jin Y (29 April 2020). Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. The Lancet: S0140673620310229. Doi:10.1016/S0140-6736(20)31022-9.             

Eastman RT, Roth JS, Brimacombe KR, Simeonov A, Shen M, Patnaik S, Hall MD (May 2020). Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19. ACS Cent. Sci. Doi:10.1021/acscentsci.0c00489.

Ferner RE, Aronson JK (April 2020). Remdesivir in covid-19. BMJ. 369: m1610. Doi:10.1136/bmj.m1610.

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