Beyond Paxlovid for covid-19: Scientists are scrambling to make better covid antiviral medications

Antiviral drugs like remdesivir, molnupiravir and Paxlovid have undoubtedly saved lives and reduced the suffering wrought by covid-19 since they began rolling out in fall of 2020.

“I think the technical word to describe [the current covid] drugs would be suboptimal,” said Luis Schang, a virologist at Cornell University. The drugs, all of which stem from antivirals developed before SARS-CoV-2 existed, have been a first good stab at beating back the virus in the body, he said, “but they all have limitations.”

But in the history of antiviral drugs, less-than-perfect initial stabs are the norm, experts said, drawing parallels with efforts to develop effective treatments for conditions like HIV and hepatitis C.

“The first drug that we used against HIV, to be quite honest, was miserable,” Schang said. AZT, first approved in 1987, caused serious side effects, and its effectiveness wore off quickly — sometimes in just days — as the virus evolved resistance. It took nearly a decade of research for scientists to develop a breakthrough triple-drug therapy in 1996 that combined several antiviral drugs to combat resistance. But the regimes involved complicated dosing and serious side effects that hampered their use. Now, there are more than 30 antiviral drugs for HIV, and it’s possible to treat the condition with just one pill a day.

Those first-generation drugs were better than nothing, but it took years of research to find better options. “As the second-, third- and fourth-generation drugs were developed, the drugs got more potent, had less side effects and can be given less often,” said Sara Cherry, an immunologist at the Perelman School of Medicine at the University of Pennsylvania. “It really speaks to the fact that every development of a new drug can help mitigate all the things about the first generation that were imperfect.”

From the earliest days of the pandemic, researchers and pharmaceutical companies have suspected that the first covid drugs to market wouldn’t end up being the final word on treating the disease.

The second-generation covid antivirals closest to approval will likely target similar aspects of the coronavirus as existing drugs, but better. Pfizer is reportedly working on an improved version of Paxlovid that would make it less problematic for people taking other medications, and the Japanese company Shionogi developed a once-a-day drug that works similarly to Paxlovid (which must be taken multiple times a day), that could be approved within months. An infusion of research money into a long-neglected field is fueling experimentation, with many labs developing new ways of stopping SARS-CoV-2, some of which might work against many other viruses.

“In the future, I think that we’re going to have more drugs against similar targets, we’re going to have drugs against new targets. And hopefully, we’ll have combinations in the future that will really slam the virus,” Cherry said.

Many ways to stop a virus

Viruses are little more than tangled strands of genetic material (RNA, in SARS-CoV-2′s case) enclosed in a protein shell. They don’t have the ability to reproduce on their own and instead hijack the machinery of their hosts to copy themselves.

Antiviral drugs are designed to gum up this process. “Viruses that aren’t reproducing don’t cause acute disease, typically,” said Jeffrey Glenn, a gastroenterologist and molecular virologist at Stanford University. “So, we want to interfere with their ability to reproduce themselves.”

Most existing antiviral drugs, for any disease, aim to disrupt something about the virus itself. Many target viral polymerases, the proteins viruses use to make copies of their genetic material once they infect a host. Remdesivir, for instance, mimics the coronavirus’ genetic material, halting replication. Another common target is viral proteases, enzymes a virus needs to make proteins that make more viruses. The active ingredient in Paxlovid, which consists of two medications, inhibits a key enzyme needed to produce this replication machinery. The other ingredient slows the body’s metabolism of the active ingredient, helping it work longer.

Imperfect single antivirals can also foster the evolution of drug-resistant strains of a virus. By knocking down susceptible strains in an infected individual, the antiviral can give resistant strains a leg up, allowing them to flourish within that individual and spread. “The single drugs initially used for HIV evolved resistance generally quickly,” said Matthew Frieman, a coronavirus researcher at the University of Maryland. “It wasn’t until they started combining two and three and four drugs together, these drug cocktails, that scientists learned this worked much more efficiently.”

Combining multiple antiviral drugs makes it much harder for a virus to evolve resistance, since it’s being hit from many different angles at different stages of the replication cycle, Frieman said. The strategy is often simply more effective, too. “By hitting it at multiple steps in life cycle, you can really enhance the effects of any one of these drugs individually,” he said. “You can also generally use less of each drug, which can reduce side effects.”

Identifying drugs that might work together is one crucial step, and scientists have already begun testing different combinations in the lab. “The other part is combining together drugs developed by different companies,” Frieman said. “It becomes an issue of money and patent rights, which can be difficult.” Altogether, the process of developing combination therapy can take many years, he said.

Finding new targets

Most antiviral drugs, for any condition, target two key factors of viral replication, polymerases and proteases. “I expect the next generation [of covid antivirals] will come from optimized protease and polymerase inhibitors,” said Schang. Some versions, which are easier to take and have fewer drug interactions, might be approved within months. But many scientists are starting to think beyond these targets.

“Antiviral therapies are heavily biased toward protease inhibitors and polymerase inhibitors,” said Schang, “and that’s resulted in a relative scarcity of chemical scaffolds that are known to have antiviral activity. That’s a major limitation moving forward. We have to have more chemical diversity.”

There are many ways to throw a wrench in viral replication. For example, before a virus can replicate, its viral RNA must be unwound by enzymes called helicases.“ There are lots of programs trying to develop helicase inhibitors against SARS-CoV-2,” Cherry said. Other scientists are working on ways of creating chinks into the coronavirus’ armor, designing antivirals that blow apart the protein shell that encases viral genetic material.

Other researchers are trying to design drugs that deprive viruses the opportunity to usurp our cells, by latching onto parts of human cells that the virus hijacks to invade or blocking access to human cellular components the virus needs to reproduce.

The approach is relatively new, and few drugs use it, but so-called host-directed antivirals could have advantages, said Glenn of Stanford. “Since you’re targeting something not under the virus’ control, we predict a high barrier to development of resistance,” he said. Such drugs might work against other viruses too. “If one virus has evolved to depend on a certain host function, it’s likely others have too,” he said.

Efficacy and ease of use aren’t the only factors that will shape the next iterations of covid antivirals. To be maximally effective, the drugs need to relatively inexpensive and easy to manufacture and distribute worldwide, Cherry said. “That’s actually not so trivial,” she said, but is key to ensuring the kind of equitable access that represents the world’s best bet toward controlling the pandemic.

But with unprecedented funding and interest in antivirals, many researchers are optimistic. Not only might the next generations of SARS-CoV-2 antivirals transform the nature of the pandemic, they might bolster our antiviral arsenal such that we’re better prepared for the next major infectious disease threat. “There’s no limit to the creativity and novelty of all these new targets,” Frieman said. “Which ones work and which ones won’t work, I don’t know, but I think that the future is really bright for the number of antivirals that will be developed in the next decade.”