Why scientists are racing to develop more COVID antivirals

Pharmacy shelves worldwide are being stocked with COVID-19 antiviral drugs like Paxlovid (pictured) and molnupiravir.Credit: YONHAP/EPA-EFE/Shutterstock

The introduction of COVID-19 vaccines in early 2021 marked a major turning point in the fight against the global pandemic. Another major milestone came late in the year with the approval of two oral antiviral treatments — molnupiravir and paxlovid — that promise to reduce COVID-19 hospitalizations and deaths. But as these pills slowly make their way into pharmacies around the world, researchers are already looking at the drugs they could replace.

“These are our first-generation antivirals against coronaviruses,” says Sara Cherry, an immunologist at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. Our experience with antivirals for other diseases like hepatitis C and HIV proves that “we can always do better with time,” she adds.

Clinical trial data showed that molnupiravir, developed by pharmaceutical company Merck, based in Kenilworth, New Jersey, and biotechnology company Ridgeback Biotherapeutics of Miami, Florida, reduced hospitalizations and deaths by 30% compared to people taking placebos. Meanwhile, Paxlovid (nirmatrelvir and ritonavir), made by New York City-based Pfizer, reduced hospitalizations and deaths by 89%. UK regulators approved molnupiravir in November and paxlovid in December, and US regulators granted emergency use authorizations for both drugs in December. Other countries have followed suit with their own approvals, and many are negotiating with drugmakers to buy grades of the drugs or make their own generic versions.

At the moment the pills are in short supply. Drugmakers are still ramping up production of the antivirals that are in high demand to treat the highly transmissible Omicron variant. But as they become more widely available — and when their clinical trial data is confirmed in the real world — the pills will become important tools in preventing people from getting seriously ill with COVID-19, says Cherry.

It’s too early to say if SARS-CoV-2 is likely to develop resistance to these first-generation antivirals, says Tim Sheahan, a coronavirusologist at the University of North Carolina at Chapel Hill. Although its sky-high replication rate is a breeding ground for mutations, the virus also causes acute infections that allow relatively little time for resistance-causing mutations to accumulate.

But the risk of resistance is particularly high with “monotherapies” such as molnupiravir and paxlovid, which each target only part of the virus. Because of this, it’s imperative to develop new antiviral drugs that target multiple targets, or ones that can be combined into a single treatment to attack the virus on multiple fronts, Sheahan says.

A race against odds

Successful antivirals typically target two key elements of a virus’ biological machinery, a polymerase and a protease, both of which are essential for viral replication. The current COVID pills are no exception: Paxlovid inhibits the main protease of SARS-CoV-2, while molnupiravir tricks its RNA polymerase into incorporating part of the drug into the virus’ RNA, creating so many errors that it cannot can survive. A third drug — remdesivir, developed by Gilead, based in Foster City, Calif. — inhibits RNA polymerase, but treatment is expensive and currently requires IV fluids for three consecutive days, making it unavailable to many people.

Unfortunately, molnupiravir’s aggressive nature means it may not be advisable to include it in combination therapy, says Luis Schang, a virologist at Cornell University in Ithaca, New York. If treatment doesn’t completely eradicate the virus in a patient, some of the RNA errors it creates could inadvertently confer resistance on the virus to the other drug in the combination. For that reason, a key priority for researchers is finding an accessible drug that effectively blocks the virus’ RNA polymerase, he says, which could be used in partnership with a protease inhibitor such as Paxlovid. One option could be an oral version of remdesivir, which Gilead is currently testing.

Other antiviral drug candidates are slowly working their way through the clinical trials pipeline, says Carl Dieffenbach, director of the Division of AIDS at the US National Institutes of Allergy and Infectious Diseases (NIAID). He says one promising candidate is a protease inhibitor developed by Shionogi & Company, based in Osaka, Japan, and the University of Hokkaido in Japan, and is currently in phase II/III clinical trials in Asia. The candidate targets the same protease as Paxlovid, but would only require taking a single pill daily.

This simpler regimen could help stave off the rise in resistance, says Cherry. Unfinished treatments can accelerate drug resistance by allowing the virus to build defenses against the drug while it continues to multiply and wreak havoc in the body. Both Molnupiravir and Paxlovid consist of multiple pills that need to be taken twice a day for five consecutive days. “The second time people take something multiple times a day when they’re sick is when they have compliance issues,” says Cherry.

target practice

Researchers should also develop treatments that target other parts of the virus, Schang says. “This time we got lucky with a virus that encodes both a polymerase and a protease, and here we are two years later with just a suboptimal arsenal,” he says. “We really need to identify and validate new targets for antivirals so that next time we can [pandemic] happens, we have a much broader pipeline to choose from.”

Other potential targets include another protease in SARS-CoV-2 called PLprofessional, and an enzyme called methyltransferase that stabilizes the virus’ RNA, says Matt Hall, director of the early translation division at the US National Center for Advancing Translational Sciences (NCATS). Clear Creek Bio, a biotechnology company based in Cambridge, Massachusetts, announced on Jan. 6 that it will work with NCATS to develop an oral drug that targets PLprofessional Enzyme.

Dieffenbach says the researchers would most like to identify targets common to entire families of viruses and inhibit them with a single drug. This would potentially allow health authorities to quickly deploy an effective antiviral the next time a novel virus with pandemic potential emerges.

Developing such broad-spectrum drugs will require significant public and private investment, as well as collaboration between pharmaceutical companies, Hall says. Calls for such efforts went unheeded after the SARS-CoV outbreak in 2003, he adds, but the recent pandemic has underscored the need for action. Last year, the United States gave NIAID $1.2 billion to open the Antiviral Drug Discovery Centers for Pathogens of Pandemic Concern, which will fund basic research to develop antiviral drugs for seven virus families. According to Hall, this gives him hope that antiviral research will continue even as the COVID-19 pandemic subsides.

But all antivirals have an inherent limitation, Dieffenbach says: They must be taken within days of infection to stop a virus from multiplying. Antivirals are only effective when people realize they may be sick and have access to tests that provide a timely diagnosis. “We can build the best medicines in the world, but if people don’t understand that they have to get on board quickly, they’re useless,” says Dieffenbach. “Pills don’t take themselves.”


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