Breakthrough drug-like molecule could prevent the flu, study finds

Current flu medications are designed to target the virus once it has already begun to establish an infection in the body. However, a groundbreaking study by scientists at Scripps Research and the Albert Einstein College of Medicine has introduced a new approach.

These researchers have developed drug-like molecules that could potentially prevent influenza infection altogether by blocking the initial stage of viral entry into the body’s respiratory cells.

The new inhibitors specifically target hemagglutinin, a protein found on the surface of type A influenza viruses. This significant discovery was published in the Proceedings of the National Academy of Sciences.

“We’re trying to target the very first stage of influenza infection since it would be better to prevent infection in the first place,” says Ian Wilson, DPhil, the Hansen Professor of Structural Biology at Scripps Research. He adds, “These molecules could also be used to inhibit the spread of the virus after one is infected.”

Although the inhibitors require further optimization and testing before they can be used as antivirals in humans, the researchers are optimistic about their potential. Unlike vaccines, these inhibitors likely wouldn’t need to be updated yearly, which could revolutionize how we approach seasonal flu prevention and treatment.

In their earlier research, the team had identified a small molecule, F0045(S), with a limited capacity to bind and inhibit H1N1 type A influenza viruses.

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“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,” explains Dennis Wolan, PhD, senior principal scientist at Genentech and former associate professor at Scripps Research.

The current study focused on optimizing the chemical structure of F0045(S) to create molecules with better drug-like properties and a stronger binding ability to the virus. The team used “SuFEx click-chemistry,” a method developed by co-author and two-time Nobel laureate K. Barry Sharpless, PhD.

This technique allowed them to generate a large library of candidate molecules with various modifications to F0045(S)’s original structure. From this library, they identified two molecules—4(R) and 6(R)—with superior binding affinity compared to F0045(S).

Wilson’s lab then produced X-ray crystal structures of 4(R) and 6(R) bound to the flu hemagglutinin protein. This step was crucial for identifying the molecules’ binding sites, understanding the mechanisms behind their superior binding ability, and pinpointing areas for further improvement.

“We showed that these inhibitors bind much more tightly to the viral antigen hemagglutinin than the original lead molecule did,” says Wilson. “By using click-chemistry, we extended the compounds’ ability to interact with influenza by making them target additional pockets on the antigen surface.”

When tested in cell culture, 6(R) demonstrated a remarkable improvement in antiviral properties and safety. It was non-toxic and showed more than 200-times improved cellular antiviral potency compared to F0045(S).

Building on these promising results, the researchers used a targeted approach to further optimize 6(R), leading to the development of compound 7, which exhibited even better antiviral ability. “This is the most potent small-molecule hemagglutinin inhibitor developed to date,” says 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.

Looking ahead, the team plans to continue optimizing compound 7 and to test the inhibitor in animal models of influenza. “In terms of potency, it will be hard to improve the molecule any further, but there are many other properties to consider and optimize, for example, pharmacokinetics, metabolism, and aqueous solubility,” says Kitamura.

Currently, the inhibitors developed in this study only target H1N1 strains of influenza. Therefore, the researchers are also working on developing equivalent drug-like inhibitors to target other strains of influenza, such as H3N2 and H5N1. This work could potentially lead to a comprehensive approach to preventing and treating various types of influenza.

By targeting the virus at its earliest stage of infection, these new inhibitors hold the promise of not only preventing the flu but also offering a robust tool in the ongoing battle against seasonal flu outbreaks. The next steps in this research will be crucial in determining the feasibility and effectiveness of these inhibitors in real-world applications.

Note: Materials provided above by The Brighter Side of News. Content may be edited for style and length.

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