Scientists from the University of Alberta have published findings that the antiviral drug remdesivir prevents replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by inhibiting RNA replication. The study, published in April 2020 in the Journal of Biological Chemistry, follows on the heels of earlier reports from the same lab in February, showing the drug's effectiveness against the related Middle East Respiratory Syndrome (MERS) virus.
Many attempts are being made to develop an effective cure for the virus responsible for the COVID-19 pandemic that has affected over 2 million people globally so far. The World Health Organization (WHO), as well as independent clinical researchers across the globe, are studying the effectiveness of remdesivir.
What is remdesivir?
Remdesivir was first developed by Gilead Sciences in 2014 as a treatment for Ebola and Marburg viruses. However, the implications for the drug for similar single-stranded RNA viruses were quickly realized, as it promises to be a broad-spectrum drug against this category. The absence of a vaccine has forced researchers all over the world to probe all existing therapies, which could be useful in treating the virus.
"We obtained almost identical results as we reported previously with MERS, so we see that remdesivir is a very potent inhibitor for coronavirus polymerases," said Matthias Götte of the University of Alberta.
Götte is no newcomer to the field of viral polymerases, having previously researched human immunodeficiency virus (HIV) and hepatitis C virus (HCV). However, after the WHO issued a list of top pathogens that have the potential to cause outbreaks in 2015, which included coronaviruses, the lab switched to studying those viruses. This meant that his lab had a head start when it came to researching antiviral treatment for SARS-CoV-2.
Novel Coronavirus SARS-CoV-2 Colorized scanning electron micrograph of an apoptotic cell (blue) infected with SARS-COV-2 virus particles (red), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID
How does remdesivir work?
Götte explains in the research paper how the antiviral targets the polymerase of the novel coronavirus, called viral RNA-dependent RNA polymerase (RdRp). This is required for building the viral genome, which is an essential step in its replication. Remdesivir is a nucleotide analog, that is, a 'look-alike' to the nucleotides that are the building blocks of the genome.
The study analyzed purified active RdRp from the SARS-CoV-2 virus, made up of the non-structural proteins nsp8 ad nsp12. Examination of the way these enzyme works shows that it is efficient at picking up remdesivir in its active triphosphate form and building it into the growing RNA strand. When it is incorporated at position i, the chain stops forming three nucleotides later. In other words, when the coronavirus polymerase hooks up to the drug instead of the real nucleotides, it is inhibited three steps later. This phenomenon is called "delayed chain termination," and could be the mechanism through which the drug operates.
"These coronavirus polymerases are sloppy, and they get fooled, so the inhibitor gets incorporated many times, and the virus can no longer replicate," Götte explains. The same results were obtained with the SARS-CoV and MERS-CoV viruses as well.
How is remdesivir better than other antivirals?
The uniquely useful feature of remdesivir is that it is preferentially incorporated into RNA over its natural counterpart, adenosine triphosphate. This makes it superior in this respect to other antivirals in their triphosphate form, such as sofosbuvir (approved for hepatitis C therapy), favipiravir, and ribavirin (both used in several viral infections).
However, remdesivir is also target-specific, in that it is not as easily incorporated by the Lassa virus RdRp, though the latter is a relative of the SARS-CoV-2, and does not inhibit the synthesis of the RNA chain.
The study carries clinical significance - its results mean that remdesivir can be classified as "direct-acting antiviral" (DAA) against SARS-CoV-2, a term first used to describe newer drugs that inhibit hepatitis C virus (HCV) life cycle steps. This could strengthen the evidence for the clinical efficacy of the drug if ongoing clinical trials around the world confirm its usefulness.
Götte cautions against premature rejoicing, explaining that since the drug's use was limited to "compassionate" use in severely ill COVID-19 patients, its effectiveness cannot be established until a randomized controlled trial against a placebo or another drug is concluded. "We are desperate, but we still have to keep the bar high for anything that we put into clinical trials," he said.
The future for remdesivir
The World Health Organization has fast-tracked remdesivir into clinical trials, along with other promising drugs. Currently, around a dozen countries are carrying out simultaneous drug trials on hospitalized COVID-19 patients, with results being expected by April or May.
Götte states that he has faith in the high amount of research being carried out globally as well as the unprecedented coordination between researchers, which he says should speed up the process of finding a cure. He confesses to being disappointed that several promising antivirals discovered during the SARS epidemic of 2003, which could have been effective in treating COVID-19 patients as well, were never tested and produced commercially. This was primarily due to the financial constraints of producing new drugs – in the neighborhood of 10 billion dollars. However, Götte points out that, in light of the economic costs of the COVID-19 pandemic, this is a small price to pay to produce an effective antiviral. He says that "This time around, it's obvious that we have to cross the finish line." In other words, any effective drugs that are discovered should be pushed through to commercially produced widely available therapies this time.
Gordon, C. J. et al. (2020). Remdesivir is a Direct-Acting Antiviral That Inhibits RNA-Dependent RNA Polymerase from Severe Acute Respiratory Syndrome Coronavirus 2 With High Potency. Journal of Biological Chemistry. doi: 10.1074/jbc.RA120.013679, https://www.jbc.org/content/early/2020/04/13/jbc.RA120.013679.abstract