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Hot pursuit
Molnupiravir began as a possible therapy for Venezuelan equine encephalitis virus at Emory University’s non-profit company DRIVE (Drug Innovation Ventures at Emory) in Atlanta. But in 2015, DRIVE’s chief executive George Painter offered it to a collaborator, virologist Mark Denison at Vanderbilt University in Nashville, Tennessee, to test against coronaviruses.
“I was pretty blown away by it,” Denison remembers. He found that it worked against multiple coronaviruses: MERS and mouse hepatitis virus. Painter also recruited his collaborator Plemper to test the drug against influenza and respiratory syncytial virus.
After the pandemic hit, however, plans changed. DRIVE licensed the compound to Ridgeback Biotherapeutics in Miami, Florida. Plemper, too, pivoted to coronaviruses, and tested the compound in ferrets. It silenced the virus’s ability to replicate, he says, but it also suppressed the virus’s transmission from infected ferrets to uninfected ones. Merck’s data hinted that might also be true in humans: molnupiravir appeared to shorten the duration of SARS-CoV-2’s infectivity in trial participants with the virus.
Molnupiravir, like remdesivir, is a nucleoside analogue, which means it mimics some of the building blocks of RNA. But the compounds work in entirely different ways. When SARS-CoV-2 enters a cell, the virus needs to duplicate its RNA genome to form new viruses. Remdesivir is a ‘chain terminator’. It stops the enzyme that builds these RNA ‘chains’ from adding further links. Molnupiravir, on the other hand, gets incorporated into burgeoning RNA strands and, once inside, wreaks havoc. The compound can shift its configuration, sometimes mimicking the nucleoside cytidine and sometimes mimicking uridine. Those RNA strands become faulty blueprints for the next round of viral genomes. Anywhere the compound gets inserted and that conformational shift happens, a point mutation occurs, Plemper told Nature. When enough mutations accumulate, the viral population collapses.
“That is what we term lethal mutagenesis,” he adds. “The virus essentially mutates itself to death.”
And because the mutations accumulate randomly, it’s difficult for viruses to evolve resistance to molnupiravir — another plus for the compound.
But the compound’s mutagenic potential in human cells — the possibility that it could incorporate itself into DNA — does raise safety concerns, some researchers say. Merck has not released any detailed safety data yet, but “we’re very comfortable that the drug will be safe if used as intended”, said Daria Hazuda, Merck’s vice-president of infectious-disease discovery and chief science officer, at a press briefing in early October.
Waiting in the wings
Other antivirals are in the works. Gilead Sciences is developing a pill version of remdesivir. And Denison suspects that if the antiviral were given to people as early as molnupiravir is — when symptoms have only just appeared and viral loads are high — it would be similarly effective. In a study presented at IDWeek, a virtual meeting of infectious-disease specialists and epidemiologists held early in October, researchers reported results of administering infusions of remdesivir to people in the early stages of COVID-19 every day for three days. The number of participants in the study was small, but remdesivir appeared to reduce hospitalisations by 87% in people at high risk of developing COVID-19.
Biotech firm Atea Pharmaceuticals in Boston, Massachusetts, also has an antiviral in the works. It was testing a nucleoside analogue against hepatitis C in a clinical study when SARS-CoV-2 emerged. The pandemic paused the trial, so Atea decided to switch its focus to COVID-19. Now it has partnered with Roche in Basel, Switzerland, to develop its compound.
Pfizer, based in New York City, had a bit of a head start too. The company had been developing antivirals against SARS since the early 2000s, but shelved them when the outbreak ebbed. When the COVID-19 pandemic began, “they just blew the dust off”, Luly says. Researchers are currently testing a pill form of a compound that has a mechanism of action similar to those original versions. It is in phase 2/3 trials for treating people who are newly infected.
