In a perfect world, we wouldn’t get the flu, wouldn’t require annual vaccinations, and could even get rid of the virus once it has infected us. Thanks to researchers who have found an effective molecule that can stop influenza A from entering our systems.
Researchers from the Albert Einstein College of Medicine and Scripps Research have discovered drug-like molecules that can prevent any extremely contagious flu virus mutation from occurring at the first signs of infection. Ian Wilson, the Hansen Professor of Structural Biology at Scripps Research, says, “We’re trying to target the very first stage of influenza infection since it would be better to prevent infection in the first place, but these molecules could also be used to inhibit the spread of the virus after one’s infected.”
Vaccination is the best line of defense against the flu, yet immunity is not guaranteed because the virus can change its course each season. Even a minor illness can trigger severe immune system reactions, particularly in older or immunocompromised individuals.
Currently, efforts are being made to stop influenza A viruses from infecting respiratory cells by blocking a protein on their surface using a drug-like inhibitor. This discovery expands upon earlier studies that found a tiny chemical, F0045(S), that had the potential to bind to H1N1 influenza A viruses, although not very well. Through structural modifications of F0045(S), researchers created molecules that bind to the virus much more firmly.
“We began by developing a high-throughput hemagglutinin binding assay that allowed us to screen large libraries of small molecules rapidly and found the lead compound F0045(S) with this process,” says Dennis Wolan, senior principal scientist at Genentech and former associate professor at Scripps Research.
By adjusting F0045(S), researchers used SuFEx click-chemistry—a technique invented by two-time Nobel laureate K. Barry Sharpless—to generate a library of potential molecules. They found 4(R) and 6(R), two promising molecules, had much improved binding characteristics. Further optimization was made possible by discovering these molecules’ precise binding areas on the virus’s hemagglutinin protein by X-ray crystal structures.
“We showed that these inhibitors bind much more tightly to the viral antigen hemagglutinin than the original lead molecule did,” said Wilson. “Using click-chemistry, we extended the compounds’ ability to interact with influenza by making them target additional pockets on the antigen surface.”
Molecule 6(R) is a promising option for drug to prevent flu since it binds 200 times more effectively than F0045(S) and is non-toxic. Subsequently, 6(R) was improved to create compound 7, which had even more antiviral efficacy.
“This is the most potent small-molecule hemagglutinin inhibitor developed to date,” said Seiya Kitamura, who worked on the project at Scripps Research and is now an assistant professor at the Albert Einstein College of Medicine.
Compound 7 is currently being tested on animals, and the team is concentrating on improving its pharmacokinetics, metabolism, and solubility. Researchers are also investigating similar approaches to target other types of the virus, such as H5N1, often known as avian influenza, which might become highly contagious and seriously harm humans.
This groundbreaking research was published in The Proceedings of the National Academy of Sciences.
Source: Scripps Research Institute
