A coronavirus vaccine may not arrive for at least a year—so what are the chances of finding a useful therapy that could stave off the worst effects of the virus in the meantime?

Earlier coronavirus outbreaks like SARS and MERS raised warning flags for public health officials. Fortunately, they also alerted the biological research community that this large family of viruses was worth studying in more detail. Recent research has built on a large body of knowledge about coronaviruses that have long caused significant diseases in livestock, and so SARS-CoV-2 does not arrive as a total unknown. Indeed, we are actually in a decent position to understand what might make a good potential therapy.

While some of the therapies being tested may seem random—we're trying chloroquine, an antimalarial drug?—there's serious biology behind what's being done.

Genes without DNA

A basic challenge confronts all viral therapies: most viruses have just a handful of genes, and they rely on proteins in the cells they infect (host cells) to perform many of the functions needed to reproduce. But therapies that target host cell proteins run the risk of killing uninfected cells, making matters worse. So antiviral therapies usually target something unique about the virus—something important enough that a few mutations in the virus won't make the therapy ineffective.

Those of you who didn't sleep through high school biology may remember that genetic information is carried by DNA. When a protein needs to be built, the relevant bit of DNA is read and the cell makes a temporary copy of the information using a very similar chemical called RNA. This piece of RNA is then translated into a sequence of amino acids, which form the protein. While there are some exceptions to this—many RNAs perform important functions without ever being translated into proteins—all RNA in our cells is made by transcribing a DNA sequence.

But we've known for a long time that this process doesn't hold for viruses. Many viruses, including HIV and the influenza virus, use RNA for their basic genetic material. The coronavirus is also an RNA virus; it consists of a single, 30,000-base-long RNA molecule.

This is a problem for the virus. The host cells it infects only have proteins that copy DNA, not RNA, so how can more copies of the virus get made?

Target: reproduction

It turns out that the virus carries its own solution with it. When virus' RNA genome first enters a cell, it interacts with the host's protein-making machinery, using it to make proteins that can copy RNA molecules.

These RNA-copying proteins, called "polymerases," make an enticing target for therapies. Because host cells don't naturally have them, therapies that target these RNA-making proteins should have a lower chance of off-target effects. Block these RNA polymerases, and the virus can no longer reproduce, stopping an infection. That's the good news.

The bad news is that DNA and RNA are so closely related that it can be difficult to make a drug that affects only one type of polymerase. We saw this with some of the first therapies against HIV, which targeted the enzymes that copied the virus' RNA genome: they did slow the virus down, but they also harmed any rapidly dividing cells in the host.

So the work is tricky. But many such drugs have been developed that don't interact as well with our own DNA polymerases. Some have even been tested for safety in humans, since they were developed for earlier threats like HIV or Ebola. Now, several are being quickly tested against coronavirus.

One such drug, remdesivir, was originally developed in the hope that it would limit Ebola virus and its relatives. While that hasn't worked out, the drug was safe for human use and showed promise in its ability to limit the spread of another coronavirus (MERS-CoV) in cultured cells. As a result, it was quickly tested against SARS-CoV-2, and the results were also positive. The National Institutes of Health started a clinical trial against COVID-19 in February.

Vincent Racaniello is a faculty member at Columbia University and the host of the This Week in Virology podcast. He believes that RNA polymerases are so similar across a range of coronaviruses that we might find a single molecule that inhibits them all. To Racaniello, our response to SARS and MERS wasted a great opportunity.

"We could have had a broadly acting antiviral that targeted RNA polymerase by now," he told Ars. "We could have had people isolating the gene from various bat coronaviruses and doing screens to see if we could find compounds that could have inhibited them all. That's the kind of thing that's doable and should have been done. And if we had such antivirals ready, they could have been used right at the onset in China."

Target: processing

RNA copying polymerases aren't the only potential therapeutic targets for a coronavirus. Their RNA polymerases are initially made in forms that aren't fully functional; instead, they must have small pieces snipped out in order to adopt their mature configuration. Coronavirus RNA therefore encodes two or three proteins that do this cutting. They belong to a class of proteins collectively termed "proteases" for their protein-cutting ability. Proteases typically have a very specific site where the cutting takes place, and any chemicals that can fit into this site might shut the protease down. Not surprisingly, such chemicals are called protease inhibitors.

This approach has been used successfully against other viruses, notably including HIV. Scientists have now found that protease inhibitors targeted to HIV might have activity against coronavirus, despite the fact that these viruses are unrelated.

Because proteases are present in small numbers in infected cells and have a catalytic activity that depends on a single, specific site, Racaniello views them as some of the most promising targets for therapies. We've also got large libraries of chemicals that are known to inhibit similar proteins, many of which are already approved for use in humans. So, while the news around protease inhibitors has been somewhat limited, expect it to pick up dramatically as more of these molecules are screened.

Target: packaging

After replication, viral RNA can't continue an infection until it is packaged up into a mature virus and gets outside of the host cell. This requires special packaging proteins. (In coronavirus, these proteins do double duty by also helping the viral RNA link up with its copying enzymes.) This packaging step would seem to provide a great opportunity for targeted therapy, as disrupting it should limit the amount of functional virus that gets made and exported from any particular cell.

But drugs that try to block viral packaging are rare—Racaniello can only think of one, a treatment for Hepatitis B that causes the mature virus particles to form without any genetic material inside. "That's been a very unusual antiviral," Racaniello said. "There's no other like it." Part of the problem, he said, is that structural proteins like this are present in high numbers, since they're part of every single virus particle that's produced. And you have to interfere with all these copies to be effective.

Another problem is that the interactions among proteins and genetic material during packaging of a virus tend to involve extensive contacts between multiple molecules. These are a bit harder to disrupt specifically, and doing so may require large molecules that don't diffuse in and out of cells well. So, while we know which protein binds to the RNA and helps package it inside the virus particle, this protein is not an obvious target for therapies.

It's also hard to disrupt newly packaged viruses as they are moved out of the cell. Once packaged, coronaviruses leave their host cell via an export system that's normally used to send material to the cell's surface (a process called exocytosis). This process is fairly generic—it works with a huge variety of proteins in addition to those encoded by coronaviruses—making it vital for cell survival. As a result, there are not many places where we can intervene without shutting down exocytosis in healthy cells as well.