During the throes of the COVID-19 pandemic, Anne Moscona didn’t feel safe going to a restaurant or catching a flight. She wished she had felt confident in being able to see her immunocompromised relatives without inadvertently spreading the new coronavirus to them. All of this made her work personal: For the past decade, Moscona, a molecular virologist, has been searching for compounds that can stop viruses in their tracks, before pathogens infect even a single cell in the human body.
Now, Moscona, at Columbia University in New York City, and her colleagues have focused on a compound that might thwart SARS-CoV-2. Even better, it is simply sprayed over the nose – no needle required1.
The spray developed by the Moscona team is one of a group of nasal sprays proposed for the prevention of SARS-CoV-2 infection. The sprays will be fast-acting and will be applied frequently, perhaps once or twice a day, to the site where the virus first spreads – the lining of the nose and throat. Unlike vaccines, which train the recipient’s immune system to build long-term protection, sprays are short-lived compounds that directly block the virus’s ability to enter cells. Multiple research teams have shown that such sprays are effective in warding off SARS-CoV-2 infection in animals.
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If these compounds are effective in humans, they would be a welcome addition to the limited arsenal that researchers have developed against the virus, says Donna Farber, an immunologist at Columbia University in New York City. Vaccines protect against severe COVID-19, but are less adept at preventing infection, and current antivirals treat infections rather than prevent them. Nebulizers can offer people another way to avoid getting infected on top of — or instead of — wearing a face mask, especially in high-risk settings like hospitals and restaurants. “They are definitely worth pursuing in a big way,” she says.
Despite their promise, these sprays still have a long way to go: Funding and interest from drug companies for human trials has been limited, in part because trials to determine the effectiveness of preventative drugs are large and expensive, Moscona says. And sprays must accomplish the challenging task of covering any surface the virus might stick to, because once viral particles enter even a small number of cells, a large-scale infection can quickly develop.
Wendy Barclay, a virologist at Imperial College London, says efforts to develop preventative treatments against viruses predated the emergence of Covid-19. This research has paid off with a range of oral medications, including oseltamivir (Tamiflu), which prevents influenza infection, and tenofovir-emtricitabine, which prevents HIV infection. But, says Barkley, there are no preventative nasal sprays except for First Defense, which is designed to act as a physical barrier against common cold virus particles.
Preventive sprays have a simpler function than traditional antivirals, such as Baxlovid, that are used in the early days of an infection: Preventing a single virus particle from infecting a cell is “a much easier request than counteracting the effects of millions of viral particles,” Barclay says days after infection.
Researchers have been testing several types of compounds in nasal sprays to thwart SARS infection. Among them are small antibody-like particles called nanobodies, which disarm the virus by nesting in the nooks and crannies of viral proteins; short chains of amino acids called peptides; and small molecules that mimic proteins.
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The prophylactic developed by Moscona and colleagues, for example, is a peptide that taints the virus’s machinery for fusion with a host cell. This prevents the virus from delivering its genetic payload to the cell, thus preventing infection.
To test their peptide, Moscona and her colleagues inserted it into the noses of a ferret once a day for two days, and co-housed animals treated with another SARS-CoV-2 infected ferret. None of the six rodents that received the peptide contracted the virus, while the six rodents that received the placebo dose contracted the virus.1. Before testing the peptide in humans, Moscona wants to replicate these results in another animal model, such as mice.
Another nasal spray compound, developed by Richard Leduc, a molecular pharmacologist at the University of Sherbrooke in Canada, and colleagues is a small molecule that inhibits a host enzyme needed by the viral particles to integrate with the target cell. Leduc and colleagues found that mice given nasal doses of the compound contracted the coronavirus, but had significantly less virus in their lungs than mice that received only saline.2. Leduc and colleagues are working to increase the effectiveness of the peptide by making it more stable and selective before moving on to testing it in humans. Leduc and Moscona both work with companies to bring their products to market.
Runny nose challenge
Even if researchers find an antiviral compound that can be given as a nasal spray and prevent infection with coronavirus in humans, they still face the challenge of ensuring the compound remains in the lining of the nose long enough to be consistently effective. “Your nose and throat are designed by nature to get rid of things,” Barclay says. “You’re trying to put something in there, and your nose is running down and it’s coming out.”
Researchers can counter this by designing nebulizers to be reused frequently, but Barkley cautions that the more people need the drug, the less likely they are to stick to the regimen. And although the bulk of SARS-CoV-2 infection begins in the nose, it may be necessary to prevent covering the mouth, throat, and even the lungs, which requires delivery through a nebulizer.
However, such a spray would be an important advance, especially in places where few people are wearing face masks, Barkley says. “If we had something unseen and you managed it yourself and gave you the confidence to keep going, I think it would be a real game-changer,” she says. “We can keep the kids in school.”