Currently available flu medications only attack the virus after it has already established an infection, but what if a medication could prevent infection in the first place? Now, scientists at Scripps Research and the Albert Einstein College of Medicine have designed drug-like molecules to do just that: thwart the first stage of influenza infection.
Drug-like inhibitors prevent the virus from entering the body’s respiratory cells; Specifically, they target hemagglutinin, a protein on the surface of influenza A viruses. The findings, published in the proceedings of the National Academy of Sciences on May 16, 2024, represent an important step forward in the development of a drug that can prevent influenza infection.
“We are trying to target the first stage of influenza infection, as it would be best to prevent infection in the first place, but these molecules could also be used to inhibit the spread of the virus after infection,” says corresponding author Ian Wilson. , DPhil, Hansen Professor of Structural Biology at Scripps Research.
The inhibitors will need to be further optimized and tested before they can be evaluated as antivirals in humans, but researchers say these molecules ultimately have the potential to help prevent and treat seasonal flu infections. And unlike vaccines, inhibitors probably wouldn’t need to be updated annually.
Researchers had previously identified a small molecule, F0045(S), with limited ability to bind to and inhibit H1N1 type A influenza viruses.
“We began by developing a high-throughput hemagglutinin binding assay that allowed us to rapidly screen large libraries of small molecules and found the lead compound F0045(S) with this process,” says corresponding author Dennis Wolan, PhD, senior principal scientist at Genentech. . and former associate professor at Scripps Research.
In this study, the team set out to optimize the chemical structure of F0045(S) to design molecules with better drug-like properties and more specific binding ability to the virus. To start, the Wolan lab used “SuFEx click-chemistry,” which was first developed by two-time Nobel laureate and co-author K. Barry Sharpless, PhD, to generate a large library of candidate molecules with various adjustments to F0045(S ) the original structure. When screening this library, the researchers identified two molecules, 4(R) and 6(R), with higher binding affinity compared to F0045(S).
Next, Wilson’s lab produced union and identify areas for improvement.
“We showed that these inhibitors bind much more tightly to the viral antigen hemagglutinin than the original parent molecule,” says Wilson. “By using click chemistry, we basically expanded the ability of the compounds to interact with influenza by having them target additional pockets on the surface of the antigen.”
When researchers tested 4(R) and 6(R) in cell cultures to verify their antiviral properties and safety, they found that 6(R) was non-toxic and had 200 times greater cellular antiviral potency compared to F0045(S). . ).
Finally, the researchers used a targeted approach to further optimize 6(R) and develop compound 7, which was shown to have even better antiviral capacity.
“This is the most potent small-molecule hemagglutinin inhibitor developed to date,” says corresponding author Seiya Kitamura, who worked on the project as a postdoctoral fellow at Scripps Research and is now an assistant professor at the Albert Einstein College of Medicine.
In future studies, the team plans to continue optimizing compound 7 and test the inhibitor in animal models of influenza.
“In terms of potency, it will be difficult to further improve the molecule, but there are many other properties to consider and optimize, for example, pharmacokinetics, metabolism and aqueous solubility,” says Kitamura.
Because the inhibitors developed in this study only target H1N1 influenza strains, researchers are also working to develop equivalent drug-like inhibitors to target other influenza strains such as H3N2 and H5N1.
This work was supported by the NIH, the Nathan Shock Institute for Aging Research, and Einstein-Montefiore.