A lab technician visually inspects a vial of remdesivir at a facility in California, March 11, 2020. Photo: Gilead Sciences Inc/Handout via Reuters.
Although researchers around the world have developed different therapies to tackle COVID-19, no single method has assumed centerstage. This said, the focus of late has shifted to developing antiviral drugs that could the novel coronavirus head-on instead of quelling the symptoms of its infection or boosting the body’s immunity, etc.
Developing such antiviral drugs is an exacting task, for a few reasons.
Once a virus has entered a cell, it depends on the cell’s machinery to replicate, unlike many most bacteria. So drugs designed to target the virus could have detrimental effects on the host cells as well.
Second, continuous use of antiviral drugs could aggravate the selective pressure on the viruses. That is, after being repeatedly exposed to the same drug, viruses could begin to mutate towards becoming drug-resistant. And the drug may not work as effectively against new strains of the same virus.
Third, viruses have either DNA or RNA as their genetic material. DNA viruses have a lower mutation rate than RNA viruses due to differences between the virus’s ability to proofread its genome at the time of replication. However, while coronaviruses are RNA viruses, they’re also the exception to the rule.
The RNA of RNA viruses encodes an enzyme called RNA-dependent RNA polymerase (RdRp). RdRp – unlike DNA polymerase – is incapable of the proofreading activity that minimises mutations. However, coronaviruses also have an enzyme called exoribonuclease that encodes proofreading ability.
Somewhat recently, the American biopharmaceutical company Gilead Sciences developed an experimental drug named remdesivir. This drug has shown some encouraging results in treating COVID-19.
The novel coronavirus has four structural proteins. One of them, called the spike protein, mediates the virus’s entry into a host cell by binding to an enzyme attached to the cell, called angiotensin converting enzyme 2 (ACE2). (It’s produced predominantly by cells in human respiratory organs, which is why the virus attacks the body’s respiratory system first). Once inside, the virus releases its RNA and uses the RdRp complex to replicate its genome. Next, new virus particles are assembled and released from the infected cells to their neighbouring cells, and so forth.
Now, remdesivir is a prodrug – which means it’s inactive at the time of injection. Once it comes in contact with a host cell, the cell metabolises it into its active form, remdesivir triphosphate. This remdesivir triphosphate is similar to another substance called adenosine triphosphate, a nucleotide produced when the virus replicates its genome.
When remdesivir triphosphate is present in the cell, the virus mistakenly incorporates it into the copies of its RNA instead of adenosine triphosphate. The compound also evades the proofreader enzyme by slotting itself into the RNA at a slightly different position from where the adenosine triphosphate is supposed to be. Ultimately, the RNA synthesis process becomes stalled.
Because of how it works, it’s not feasible at first glance to administer remdesivir after a person has developed symptoms of a COVID-19 infection. This is because, by this point, the novel coronavirus would have already replicated enough to provoke the symptoms in the first place.
Remdesivir is a broad-spectrum antiviral drug originally created to treat Ebola. According to Josh Bloom, the director of chemical and pharmaceutical sciences at the American Council on Science and Health, it’s also quite difficult to produce, which does not sit well with a crisis situation.
Although it didn’t pass the phase III clinical trials, its use slightly improved survival rates among patients with Ebola. It was also shown to have a positive effect on people infected by the MERS virus.
Recently, the US National Institute of Allergy and Infectious Diseases conducted clinical trials with remedesvir, finding promising results. However, the trial has been marked by some allegations about researchers shifting the goalposts to report a more favourable outcome.
Nonetheless, the US Food and Drug Administration granted emergency approval for the use of remdesivir (this doesn’t count as a formal approval).
Researchers conducted another study in China to assess the efficacy of remdesivir and published their results on April 29. This study, however, produced conflicting results, and the researchers wrote that administering remdesivir didn’t significantly change the clinical status of COVID-19 patients.
So at this time, we need more, and more extensive, research to understand if and how remdesivir is effective against the novel coronavirus.
Niranjana Rajalakshmi is a veterinary microbiologist.