Targeted drug development takes years, but when time is short in a pandemic, scientists and clinicians turn to pharmaceuticals that have been used to treat other diseases. In rapid fashion, doctors have already deployed a number of antivirals in attempts to fight back against COVID-19 and data from their studies are now coming in. So far, trials of existing antivirals have largely focused on the drug combination lopinavir-ritonavir, which are two Food and Drug Administration–approved HIV protease inhibitors, and remdesivir, which was originally developed to treat the Ebola virus and is not yet FDA approved.
The latest study to report back from the frontlines of the pandemic has been disappointing. The results of a randomized
trial of lopinavir-ritonavir in 199 adults hospitalized with COVID-19 in Wuhan, China, that were published this week (March 18) revealed no benefit in terms of time to clinical improvement in the patients who received the drug combo versus a placebo. The findings are consistent with a
study published in January this year that showed a combination of lopinavir-ritonavir and interferon beta did not reduce lung injury a mouse model of Middle East respiratory syndrome (MERS) and only reduced virus levels in the lungs modestly in one of two experiments.
In that same study, remdesivir was much better at inhibiting the coronavirus that causes MERS in cell culture and improving respiratory symptoms in the animals, indicating that it may be a better option for treating SARS-CoV-2.
Lopinavir and ritonavir are both protease inhibitors developed specifically to treat HIV. Remdesivir, on the other hand, is a broad-spectrum antiviral. It was initially developed to treat Ebola, but it is a nucleotide analog that mimics adenosine, one of the building blocks of any RNA virus’s genome. Drugs that act as nucleotide analogs interfere with the RNA-dependent RNA polymerase, the enzyme that viruses use to copy their genomes, says Matthias Götte, a biochemist at the University of Alberta. “If you target this enzyme the virus cannot replicate anymore, so it’s a very logical target to begin with.”
We’ve done a lot of work in coronaviruses with remdesivir, but the big question is: does all of that data that we’ve generated in SARS and in MERS and in MHV, our model coronavirus, does that translate to this new virus?
—Maria Agostini, Vanderbilt University
There are three ongoing COVID-19 clinical trials at locations across China and the United States for remdesivir, which is manufactured by pharmaceutical company Gilead. Doctors in the US have also treated patients with the drug under the Food and Drug Administration’s compassionate use policy, and—while it’s not clear that it was because of remdesivir treatment—at least one patient recovered.
Remdesivir has shown promise disabling coronaviruses in the lab, too. Researchers led by Vanderbilt University’s Mark Denison and the University of North Carolina at Chapel Hill’s Ralph Baric showed in 2017 that remdesivir (then known as GS-5734) could inhibit replication of the coronaviruses that cause both severe acute respiratory syndrome (SARS) and MERS in human lung cells. The authors also found that the drug reduced viral load and improved respiratory function in a mouse model of SARS. A year later, members of the same research team published another study showing that remdesivir’s effectiveness relies on coronaviruses having an intact RNA-dependent RNA polymerase.
“We were looking for compounds that could broadly inhibit coronaviruses and the RNA-dependent RNA polymerase is, if not the most conserved protein in coronaviruses, definitely within the top two, so that makes it a good target for broad-spectrum antivirals,” says Maria Agostini, a postdoc in the Denison lab.
New work Götte and colleagues published on February 24 in the Journal of Biological Chemistry indicates that the drug, which they refer to an as an analog inhibitor, exerts these effects on the MERS coronavirus polymerase via delayed RNA chain termination. This means that when the viral polymerase incorporates the analog instead of the natural nucleotide, it adds three more nucleotides and then stops. When it can’t copy its genome, the virus can’t reproduce and make its host sick. They hypothesize that the extra three nucleotides may protect the drug from being removed by the coronavirus’s exonuclease enzyme.
In the same study, the researchers found that the MERS polymerase incorporated the mimic at a greater frequency than the natural nucleotide. This is in contrast to the Ebola polymerase, which they showed in 2019 selects adenosine triphosphate about four times as often as remdesivir.
“The more often the inhibitor is utilized instead of the natural counterpart, the more chances you have for effective inhibition. A prerequisite for inhibition is that the inhibitor needs to get into the newly synthesized RNA, and the fact that these MERS polymerases are sloppy and cannot really distinguish very well between the natural counterpart and the inhibitor, that’s an advantage,” explains Götte.
His team has already started looking into how the SARS-CoV-2 polymerase interacts with the drug. This work and animal and cell culture studies from other groups that show potent inhibition of MERS with remdesivir have Götte feeling “cautiously optimistic” that remdesivir might work for SARS-CoV-2, but there are still plenty of open questions. And other scientists have also begun to investigate the effects of remdesivir on SARS-CoV-2. In a letter published in Cell Research on February 4, remdesivir blocked coronavirus infection in monkey and human cells.
“We’ve done a lot of work in coronaviruses with remdesivir, but the big question is: does all of that data that we’ve generated in SARS and in MERS and in MHV, our model coronavirus, does that translate to this new virus?” asks Agostini. She points to the positive results of the Cell Research study, “but whether that holds true in animals and ultimately whether that holds true in people, we still have to do the experiments.”
Abby Olena is a freelance journalist based in Alabama. Find her on Twitter @abbyolena.
