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How Antivirals Create Paper Jams That Stop Viruses in Their Tracks

What do remdesivir, lopinavir and ribavirin have in common? They are antiviral drugs being tested against COVID-19. But the way in which antivirals actually work may surprise you.

Here’s a counterintuitive fact: an antiviral drug does not kill a virus. The real virus killers are the virucides, like alcohol and bleach, that tear the virus apart. It’s all in the name, with “-cide” meaning “killer”, like in genocide and homicide. But scrutinizing words too much may lead us to think that antivirals are simply out protesting in the streets that “viruses = death.” The coronavirus pandemic has forced exotic names like remdesivir and lopinavir to form on our lips, antivirals that may, we are told, help us fight our invisible enemy. But if these agents don’t slay the virus the way rubbing alcohol does, how do they work?

Viruses must make copies of themselves using an organism’s cells: antivirals, like a rogue sheet caught in the photocopy machine, simply interfere with this process. In fact, if we wanted to prevent a photocopier from making copies, we could disrupt it in a variety of ways. We could block the document feeder at the top. We could block the output tray. And we could, of course, wish for a piece of paper to get stuck on one of the many rollers inside the machine. Similarly, a virus’ replication cycle provides us with many stages at which an antiviral drug can act. A drug could prevent the virus from entering inside our cells. Another might block the release of new viruses from our cells. And any of the steps in between--from the reading of the virus’ genetic material to the assembly of the viral particles--can be targeted by an antiviral drug. Some antivirals don’t even bother with this complicated process: they stimulate our immune system to find and attack the virus. When faced with the prospect of an endless stream of photocopies, these agents simply call the local shredding company to destroy the original.

Scientists first turned to the natural world in their quest for antiviral agents, and reports in the late 1940s and early 1950s characterized some of the very first antivirals. Some were plant flavonoids, a large category of chemicals found in the human diet. Foods high in flavonoids include berries, tea, and red wine. For many decades, the main way for scientists to find natural antivirals was to put a variety of viruses into contact with extracts derived from plants, fungi, bacteria or animals and to see what would happen.

But relying exclusively on nature’s antiviral medicine cabinet led to problems. It’s one thing for a chemical to show some antiviral activity in the lab, but in the human body its concentration may be too low. After all, proteins found in cow milk have been shown to reduce replication of HIV and of other viruses, but you wouldn’t prescribe milk drinking to fight off an HIV infection. (Although some popular non-experts will jump on these types of Petri dish experiments to advise you to let food be thy medicine, failing to understand that we are not large plastic receptacles for isolated cell types.) Scientists began to modify these natural compounds in the lab to enhance their “virus castrating” prowess. But this often came at a price. Some of these altered natural antivirals showed promising results against viruses but they were toxic to our own cells. Even natural antivirals, like the aristolochic acid used by the ancient Greeks and Romans to treat snake bites and urinary problems and which has some action against herpes viruses, can prove themselves too toxic to use in humans. After all, a molecule’s natural origin is no gauge of its safety.

In 1961, Du Pont patented a molecule called amantadine and, five years later, the Food and Drug Administration (FDA) approved its use against the flu. This ushered in the era of synthetic antivirals. Amantadine is no longer recommended against the flu, as influenza viruses have become resistant to it (although it is being repurposed as a drug for Parkinson’s). One disease in particular had a major impact on the development of antivirals: HIV infection. By 2016, 90 antiviral drugs had been approved for use in humans and, of those, half were anti-HIV drugs. But because the HIV virus mutates quickly, a cocktail of antivirals is now typically administered. Each drug targets a different part of HIV’s replication cycle to ensure efficacy. A similar cocktail of antivirals was recently tested by a Chinese team against COVID-19, combining ribavirin with interferon beta-1b and lopinavir-ritonavir, to encouraging results.

All of this brings us to remdesivir, which has been in the news lately. It was created to fight hepatitis C but didn’t work very well. It has since been tried against the Ebola virus, has shown promise in the lab against a handful of other viruses, and has now received an emergency use authorization by the FDA against COVID-19. To explain how this drug is meant to stop viruses from replicating, my photocopier metaphor will have to be tortured a bit. Remdesivir mimics toner, but a specific letter made by the toner, which causes the photocopier to stop photocopying. Remdesivir’s fake “e” gets applied to the paper and a few letters later the whole process stops. This sounds great in theory but the question is: will it actually work in COVID-19 patients? We are still awaiting the proper publication of the trial that, we are promised, was positive. It is one thing for the company to claim they stopped the photocopy machine, but many of us would like to stare at the paper for ourselves.

I will leave you with a pair of sobering statistics. Only two respiratory viruses are manageable with antivirals: influenza and respiratory syncytial virus. And our antiviral armament against these viruses is made up of only eight approved drugs, including the controversial Tamiflu. I certainly hope these numbers can be boosted soon.

Take-home message:
- Antiviral drugs do not kill the virus, but they interfere with the process by which viruses make copies of themselves
- Some antivirals are molecules found in nature (either modified in the laboratory or not), while many are synthesized in the laboratory
- Half of our antiviral drugs are anti-HIV drugs and only eight antiviral drugs have been approved for use against respiratory viruses


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