A Flu-Free World: Enduring Drug Halts Influenza A

Picture a realm where flu is nonexistent, where regular vaccinations are unnecessary, and where we could even eradicate the virus from our bodies if we’re already infected. This is the goal researchers are striving for, thanks to the discovery of a highly potent molecule that could prevent influenza A from infiltrating our systems.

Researchers at Scripps Research and the Albert Einstein College of Medicine have identified drug-like compounds capable of achieving this feat: intercepting any mutation of the highly contagious flu virus during the initial phase of infection, essentially creating a biological shield for sustained immunity.

“We aim to target the initial phase of influenza infection, as preventing infection altogether is preferable. However, these molecules could also hinder the virus’s spread after infection,” explains Ian Wilson, the Hansen Professor of Structural Biology at Scripps Research, and corresponding author.

The Limitations of Current Vaccination Strategies

Currently, our primary defense against flu infection is a vaccine that doesn’t guarantee immunity. The flu virus’s adaptive nature complicates proactive measures. Even a mild flu infection can trigger a significant immune response, especially in vulnerable individuals.

Researchers have adopted a new strategy, focusing on a drug-like inhibitor that zeroes in on a protein on the surface of influenza A viruses. This action prevents the virus from establishing itself in respiratory cells and launching an attack.

This breakthrough expands on earlier findings that a small molecule, known as F0045(S), could bind to and inhibit H1N1 influenza A viruses, though not with optimal efficacy. By leveraging the chemical structure of F0045(S), researchers engineered molecules to bind more effectively to the virus.

“We initiated a high-throughput hemagglutinin binding assay to swiftly screen vast libraries of small molecules and identified the lead compound F0045(S) through this process,” explains Dennis Wolan, senior principal scientist at Genentech and former associate professor at Scripps Research, and corresponding author.

SuFEx Click-Chemistry Unveils Promising Antiviral Candidates

Employing SuFEx click-chemistry, a technique facilitating the selective synthesis of functional molecules pioneered by two-time Nobel laureate and co-author K. Barry Sharpless, the scientists constructed a library of potential molecules by modifying the structure of F0045(S). Within this library, they identified two noteworthy molecules – 4(R) and 6(R) – exhibiting superior binding properties.

Subsequent X-ray crystallography of these molecules bound to the virus’s hemagglutinin protein unveiled their binding mechanisms and locations, offering insights for further enhancement.

“We demonstrated that these inhibitors exhibit significantly stronger binding to the viral antigen hemagglutinin compared to the original lead compound,” stated Wilson. “Through click-chemistry, we expanded the compounds’ ability to interact with influenza by targeting additional antigen surface pockets.”

Of particular note, 6(R) demonstrated safe binding to its target in cell culture, exhibiting 200 times greater efficacy than F0045(S) and showing no signs of toxicity, indicating promising efficacy and safety as a potential flu-fighting drug.

Elevating Antiviral Potency

But the advancements didn’t stop there. Utilizing 6(R), the researchers refined the formulation of what they termed compound 7 – a molecule boasting even greater antiviral potency.

“This represents the most potent small-molecule hemagglutinin inhibitor developed thus far,” remarked corresponding author Seiya Kitamura, who contributed to the project at Scripps Research and currently serves as an assistant professor at the Albert Einstein College of Medicine.

The researchers are currently refining their potent virus inhibitor, compound 7, which they plan to evaluate using animal models of influenza A.

“In terms of effectiveness, enhancing the molecule further will be challenging, but there are numerous other attributes to assess and refine, such as pharmacokinetics, metabolism, and aqueous solubility,” Kitamura elaborated.

Furthermore, the team is exploring the possibility of employing a similar approach to identify targets for other virus strains, including H5N1, commonly known as avian influenza. This strain holds the potential to present a significant threat to humans if it acquires easy transmissibility.

Read the original article on: New Atlas

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