Drug-like inhibitor shows promise in preventing flu
Last reviewed: 14.06.2024
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Today, available flu drugs target the virus only after it has already established an infection, but what if a drug could prevent the infection in the first place? Now, scientists at the Scripps Institute and Albert Einstein College of Medicine have developed drug-like molecules that can do just that by interfering with the first stage of flu infection.
These inhibitors block the virus from entering the body's respiratory cells by specifically targeting hemagglutinin, a protein on the surface of influenza A viruses. These findings, published in the journal Proceedings of the National Academy of Sciences, represent an important step forward in the development of a drug that can prevent influenza infection.
“We're trying to target the very first stage of flu infection because it would be better to prevent the infection in the first place, but these molecules can also be used to inhibit the spread of the virus after infection "says lead study author Ian Wilson, DPhil, professor of structural biology at the Scripps Institute.
Inhibitors need further optimization and testing before they can be evaluated as antivirals in humans, but researchers say these molecules could ultimately help prevent and treat seasonal influenza infections. And unlike vaccines, inhibitors will likely not need to be updated annually.
Researchers previously identified a small molecule, F0045(S), with limited ability to bind to and inhibit H1N1 influenza viruses.
"We started by developing a high-throughput hemagglutinin binding assay that allowed us to quickly screen large libraries of small molecules and found the lead compound F0045(S) by this process," says lead study author Dennis Wolan, PhD, senior principal scientist at the company. Genentech and former assistant professor at the Scripps Institute.In this study, the team sought to optimize the chemical structure of F0045(S) to create molecules with better drug-like properties and a more specific ability to bind to the virus. To begin, Volan's lab used "SuFEx click chemistry," pioneered by two-time Nobel Prize winner and co-author C. Barry Sharpless, PhD, to generate a large library of candidates with various modifications of the original F0045(S) structure. When scanning this library, the researchers identified two molecules - 4(R) and 6(R) - with superior binding ability compared to F0045(S).
Wilson's lab then generated X-ray crystal structures of 4(R) and 6(R) bound to the influenza hemagglutinin protein to identify the molecules' binding sites, the mechanisms of their superior binding ability, and areas for improvement.
“We showed that these inhibitors bind much more tightly to the viral hemagglutinin antigen than the original lead molecule,” says Wilson. “Using click chemistry, we actually expanded the ability of compounds to interact with influenza by making them target additional pockets on the surface of the antigen.”
When the researchers tested 4(R) and 6(R) in cell culture to confirm their antiviral properties and safety, they found that 6(R) was non-toxic and had more than 200-fold improved antiviral activity in cells by compared to F0045(S).
Finally, the researchers used a targeted approach to further optimize 6(R) and develop compound 7, which showed even better antiviral ability.
“This is the most potent small molecule hemagglutinin inhibitor developed to date,” says lead study author Seiya Kitamura, who worked on the project as a postdoctoral fellow at the Scripps Institute and is now an assistant professor at Albert Einstein College of Medicine.
In future studies, the team plans to further optimize compound 7 and test the inhibitor in animal models of influenza.
“In terms of potency, it will be difficult to improve the molecule, but there are many other properties that need to be considered and optimized, such as pharmacokinetics, metabolism and water solubility,” says Kitamura.
Because the inhibitors developed in this study target only H1N1 influenza strains, the researchers are also working to develop similar inhibitors for other influenza strains, such as H3N2 and H5N1.