COVID caseloads have plummeted in many areas with high vaccination rates. But as the number of people being infected daily worldwide still exceeds 400,000 and the highly contagious Delta variant of the virus spreads rapidly, treatment options are limited. Two of the current best available treatments, monoclonal antibodies and the drug remdesivir, are given by infusion. Patients only benefit during the first week or so of infection, when the virus is still present and replicating in the body. These medications are expensive and often unavailable outside of large teaching hospitals. In many instances, patients are treated too late, after the disease has already shifted to a more dangerous hyperinflammatory state.

Doctors want to give pills that infected people can take conveniently at home when symptoms first appear. Toward that end, the Biden administration announced in June that it would spend more than $3 billion on a program aimed at developing next-generation antiviral therapies—not just for COVID but also for other viruses that pose a future threat.

In an interview with Scientific American, Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said he was cautiously optimistic that the new Antiviral Program for Pandemics (APP) would save lives and prevent surging hospitalizations. “It’s an ambitious program,” he said. “But if we can block the virus early on, then we can avoid the progression to advanced stages of the disease, which are so devastating to so many.”

Why is there still such a paucity of antivirals for COVID? Experts point to several factors. Antiviral research has been long neglected in general, and coronaviruses never garnered the sustained attention and funding that could have made more COVID treatments available sooner. “No one cared about coronaviruses,” says Timothy Sheahan, a virologist at the University of North Carolina at Chapel Hill. “Most of the coronaviruses that make people sick cause the common cold. And those that cause more severe disease were no longer considered a problem. The first SARS [severe acute respiratory syndrome] outbreak was over, and Middle East respiratory syndrome [MERS] wasn’t deemed a global threat.”

The COVID pandemic has now made new antiviral treatments a priority. But generating these therapies—especially direct-acting, orally administered drugs that inactivate viruses—is time-consuming. The reason monoclonal antibodies came along first is that scientists could simply follow the immune system’s lead and create synthetic versions of the natural antibodies that deflect the novel coronavirus, or SARS-CoV-2, from its host cell receptor in recovered patients. The goal of an antiviral pill is to stop the pathogen from replicating, but finding drugs that can do that without injuring the infected human cell is no easy task. Scientists start by screening thousands of compounds for their efficacy in targeting SARS-CoV-2 in cell culture. Promising candidates are then tested in animals—both to ensure that the drugs are not toxic and that they are not immediately destroyed in the body and reach tissues in the lungs and other organs in sufficient amounts. All this work takes place in high-level biosafety laboratories staffed by skilled workers, who are in short supply. “And then most of the compounds that work in cells ultimately fail in animal studies for lots of reasons,” says Sara Cherry, a microbiologist at the University of Pennsylvania’s Perelman School of Medicine. Cherry runs a biosafety lab at the university where researchers have so far screened 20,0000 compounds—including nearly every medication approved by the U.S. Food and Drug Administration—for anti-SARS-CoV-2 activity in isolated lung cells. Roughly 150 of these compounds have been selected for further evaluation in more complex lung models, “and then we’ll whittle down the top candidates for animal testing,” Cherry says.

Scientists at Emory University used this approach years ago to identify what is now the leading antiviral pill candidate for COVID: a drug called molnupiravir (also known as EIDD-2801) that was initially developed for influenza. Sheahan and other researchers, including virologists Mark Denison of Vanderbilt University Medical Center and Ralph Baric of the University of North Carolina at Chapel Hill, subsequently showed molnupiravir was effective against SARS-CoV-2 and other coronaviruses in human lung cells and infected mice. Molnupiravir has since been acquired by Merck and Ridgeback Biotherapeutics in Miami, and it is currently in clinical trials with patients experiencing mild to moderate COVID symptoms. A Merck spokesperson says that the company could file for an emergency use authorization for the drug in the U.S. later this year and in other countries in 2022.

Rachel Bender Ignacio, a physician-scientist at the Fred Hutchinson Cancer Research Center in Seattle, anticipates that the virus will develop less resistance against direct-acting small-molecule drugs such as molnupiravir than it has against monoclonal antibodies. Viruses are constantly mutating to avoid antibodies. Indeed, in June U.S. officials paused the distribution of two monoclonal antibodies developed by pharmaceutical company Eli Lilly after they stopped working against the newer COVID variants. By contrast, small molecules “target viral replication, which is a totally separate process from how their proteins interact with the immune system,” Bender Ignacio says. The viral replication machinery is “highly conserved,” meaning that it changes little over time or among different strains. According to Sheahan, a virus can only tolerate minimal damage to that machinery before replication goes awry.

Molnupiravir, which is in a class of drugs called nucleoside analogues, works by inserting itself into a newly forming viral RNA strand. The strand will then stop growing or become so heavily mutated that replication cannot continue. Scientists say molnupiravir and other direct-acting agents can also be combined in therapeutic cocktails, mirroring how drugs for viral diseases such as HIV and hepatitis C are given today. “You’re looking for drugs with different and complimentary mechanisms of action,” Sheahan says. “It’s extremely unlikely that a virus can figure out a way to get around two different drugs given at the same time.” Sheahan proposes that nucleoside analogues can, for instance, be combined with protease inhibitors, which target enzymes involved in viral replication. Along those lines, Pfizer currently has an oral protease inhibitor for COVID in early clinical trials. Known as PF-07321332, the drug “could be used at the at the first sign of infection,” a Pfizer spokesperson says.

Richard Whitley, a pediatric infectious disease specialist at the University of Alabama at Birmingham School of Medicine, says the success of the Biden administration’s new antiviral program hinges on its ability to carry promising drug candidates over a “valley of death” between basic discovery and human clinical trials. Many drugs perish in that in-between zone because pharmaceutical companies worry about potential losses. By “derisking” antiviral development with federal support, the APP will ideally help to alleviate those fears.

The Biden administration has already committed to purchasing 1.7 million courses of molnupiravir, should it be authorized for use. “Our investment in the APP follows the same strategy that allowed us to successfully develop drugs for HIV and hepatitis C,” Fauci said in his interview with Scientific American. In that case, “we had strong public-private partnerships with the pharmaceutical companies, as well as support for academic and industry partnerships aimed at finding new molecules.”

But even if successful antiviral pills materialize, Whitley says, getting them to patients during the critical first days of infection is by no means guaranteed. “Say you start feeling sick on a Saturday, and you don’t want to call your doctor,” he says. “By Monday, it might already be too late.”

Still, Whitley says he is encouraged by the sheer magnitude of the APP and its broader focus on other emerging infectious diseases. “It’s an unbelievably significant event that not only fuels the pump but generates action to come up with deliverable products,” he says. “The pharmaceutical industry can’t make enough profit to cover the costs of developing these drugs. The only way we’re going to get there is with the support of the federal government.”