In the year since the COVID pandemic began, glimmers of hope have come on the horizon. Vaccines are on the way, and the percentage of patients who die has fallen in many places as doctors have learned how to save the sickest patients.

These successes are not enough—and they overshadow the more limited progress made toward developing drugs that could prevent mild cases of the disease from worsening. Such treatments are urgently needed because many people will get sick with COVID until vaccines induce enough herd immunity in the population to keep the infections under control.

Antivirals and other drugs for early-stage illness could ideally prevent hospitalizations, shorten the duration of infectiousness and limit long-term complications from COVID. They may also prove useful against other threatening coronaviruses in the future. Yet as of this writing, only two therapies for early COVID are available, and both of them come with major logistical challenges as far as wide distribution to patients.

Regeneron’s monoclonal antibody combination for mild-to-moderate COVID, which was granted an emergency use authorization by the Food and Drug Administration in November, requires an hour-long intravenous infusion and another hour of monitoring for possible side effects. A second drug, the antiviral remdesivir, has shown promise in newly infected patients, but it requires five days of intravenous therapy. Demand for these medications, which were both administered to President Donald Trump and his allies during their illnesses, far outstrips current supplies. What doctors need are safe and effective treatments for early cases that they can give in outpatient settings “without overwhelming the health care system,” says William Fischer, a pulmonologist at the University of North Carolina School of Medicine.

Drug development efforts aimed at treatments to cripple the novel coronarvirus, or SARS-CoV-2, soon after infection are now ramping up. Physicians have a limited window of opportunity to hit the virus while it continues to replicate. Patients typically clear SARS-CoV-2 from their lungs and nasal passages within seven to 10 days, and after that, treatments aimed at disabling the pathogen become less effective. Even as viral loads plummet, immune reactions against SARS-CoV-2 can, in some patients, trigger out-of-control inflammation that destroys healthy lung tissue. At that point, treatment shifts toward drugs for severe COVID, such as dexamethasone, which ideally keep the inflammation in check.

In an interview with Scientific American, Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, described the desired characteristics of early COVID treatments. “My overwhelming preference is for direct-acting antiviral agents that can be administered orally” and that suppress the virus completely within a week or less, he said. “That, to me, is the highest priority.”

Scientists have begun on differing paths to search for these drugs. By using machine-learning algorithms, they can quickly scour chemical databases for compounds with structural properties that might work against SARS-CoV-2. Promising candidates will then move from computer-modeling studies to research in human cell lines and experimental animals. Researchers are also using new protocols designed to shuttle drugs quickly from early- to late-stage clinical trials in outpatient settings. This approach “allows us to assess more compounds in a rapid, efficient way, though we are not rushing the scientific process for any of them,” says Rachel Bender Ignacio, a physician-scientist at the Fred Hutchinson Cancer Research Center in Seattle.

Some of those drugs are repurposed medications that were initially developed for other diseases. Remdesivir, for instance, was targeted at Ebola and tested in human safety trials before being used later as a drug for COVID.

One of the current leading contenders for treating mild COVID is an antiviral pill that was previously developed for influenza. At first called EIDD-2801, the drug was found to protect mice from severe lung disease caused by two other coronaviruses—SARS-CoV and MERS-CoV. These results were from a study by researchers at the University of North Carolina at Chapel Hill (UNC) and their colleagues that was published in April. Based on those findings, a Miami-based company, Ridgeback Biotherapeutics, licensed EIDD-2801, now called molnupiravir, for safety testing in people. Ridgeback has since partnered with Merck on a mid- to late-stage clinical trial, expected to wrap up next year, to assess molnupiravir in nonhospitalized COVID patients.

Richard Plemper, a molecular virologist and biochemist at Georgia State University, has been working with the compound for years. He recently published a study showing that molnupiravir blocks SARS-CoV-2 transmission in ferrets, animals scientists use to model human coronavirus exposures. “If the ferret data are indicative of what the drug can do in people, then it suggests we’ll be able to therapeutically interrupt human transmission chains in people,” he says. “And that would be a real game changer.”

Repurposing existing drugs can also yield some surprises by finding ones that are not logical candidates to work against COVID-19. Fluvoxamine, a pill used for treating anxiety disorders, shows some promise in treating early COVID. Researchers at Washington University in St. Louis randomized 152 patients to fluvoxamine or a placebo and reported in November that none of the 80 patients who got the drug experienced worsening symptoms. By contrast, six patients in the placebo group became severely ill, and four were hospitalized. Psychiatrist Angela Reiersen, a Washington University in St. Louis psychiatrist who conducted the study, explains that fluvoxamine acts on a protein called the sigma-1 receptor, which dampens the body’s inflammatory responses to viral infection. She is now launching a larger trial across the U.S. and Canada. “We’d like to enroll people as soon as they have a positive test and some minor symptoms,” Reiersen says. “The goal is treat before week two, which is when patients generally start to deteriorate.”

Utilizing therapies that were initially developed for other purposes is not the only strategy. Drug designers have also come up with a computer-generated synthetic protein that disables SARS-CoV-2 before it gains a foothold in the body. At the University of Washington, researchers have devised from scratch proteins that bind to a spot on the virus’s spikelike protrusions. These proteins—called mini binders—deflect the virus more effectively than antibodies in human cells, according to David Baker, a computational biologist who was senior author of the study. Baker says that in unpublished research, mini binders protected hamsters against SARS-CoV-2 infection. “We see this as a prophylactic nasal spray that you could use, say, if you’re going to the airport or if you’re a medical worker going into a risky situation,” he says. Baker predicts that mini binders could enter human clinical trials against SARS-CoV-2 within six months.

In his interview with Scientific American, Fauci said that a single broad-spectrum drug that protects against many kinds of viruses is probably “a bridge too far.” Yet what can be developed is a drug that works against multiple pathogens within the same viral family—perhaps one against multiple coronaviruses.

Virologist Ralph Baric and his team at UNC have spent years working toward that goal. Much of the research is devoted to screening compounds against severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and SARS-like preepidemic bat coronaviruses in human cells and experimental animals. “When we started screening, we found some compounds that would only work against SARS and some that only worked against MERS,” Baric says. “Then we found one that worked against both.” That drug was remdesivir.

In follow-up research, Baric and his collaborator Timothy Sheahan of UNC showed the drug could also inhibit SARS-CoV-2 in human lung cells and engineered mice. Yet remdesivir’s Achilles’ heel, Baric says, “has always been that it has to be given intravenously to people, which limits uses to hospitalized patients.” In Baric’s view, that explains the drug’s inconsistent track record when it comes to speeding up COVID recovery rates: Doctors are often reluctant to admit people for treatment, he says, especially when beds are in short supply. By the time treatments begin, the virus is cleared, “and then it’s too late,” Baric adds. Remdesivir’s manufacturer, Gilead Sciences, is now developing an inhalable form of the drug that should be easier to administer in outpatient settings.

Baric contends that evidence that remdesivir, molnupiravir and other compounds are able to block multiple coronaviruses suggests that broad-based antivirals are feasible. “Imagine putting a concerted effort into developing inhibitors for the viral families most likely to cause pandemic disease outbreaks around the globe,” he says. “If we had those drugs on the shelf and ready to use immediately in an outbreak setting, we could save a ton of lives.”

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