Imagine a world in which we never got the flu, had no need for regular vaccines and could even knock the virus out of our system if an infection had already taken hold. That's what researchers are working towards, with the discovery of a super-effective molecule that could inhibit influenza A from even entering our bodies.
Scientists at Scripps Research and the Albert Einstein College of Medicine have discovered drug-like molecules that could do just that: block any mutation of the super-contagious flu virus at the very first stage of infection, essentially forming a biological forcefield for long-term immunity.
“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,” says corresponding author Ian Wilson, the Hansen Professor of Structural Biology at Scripps Research.
Right now, our best defense against flu infection is a vaccine that doesn't at all guarantee you won't get sick, and the nature of the virus and its ability to adapt each season makes it incredibly hard to get on the proverbial front foot. If you do get the flu, even if it's a milder infection, the body's natural immune response in fighting the bug can have serious ramifications, particularly in those who are immuno-compromised, have comorbidities or are older.
Here, researchers have taken a new tack, homing in on a drug-like inhibitor that targets a protein on the surface of influenza A viruses, making it impossible for the bug to find a happy home in respiratory cells where it would usually initiate its attack.
The new discovery builds on the foundation of earlier research that found a small molecule identified as F0045(S) could bind and inhibit H1N1 influenza A viruses, though not that effectively. But the scientists found that using the chemical structure of F0045(S), they could design molecules to absolutely bind to the virus.
“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, senior principal scientist at Genentech and former associate professor at Scripps Research.
Using SuFEx click-chemistry, a tool that enables selective synthesis of functional molecules, developed by two-time Nobel laureate and co-author K. Barry Sharpless, the researchers built a library of potential molecules by tweaking the structure of F0045(S). In this library, they found two molecules of particular interest – 4(R) and 6(R) – which had far better binding properties.
X-ray crystal structures of these two target molecules attached to the virus's hemagglutinin protein then revealed how and where they were able to bind to the bug – and how this could then be improved on.
“We showed that these inhibitors bind much more tightly to the viral antigen hemagglutinin than the original lead molecule did,” said Wilson. “By using click-chemistry, we basically extended the compounds’ ability to interact with influenza by making them target additional pockets on the antigen surface.”
What they found was that 6(R), in particular, was able to safely bind to its target in cell culture. Importantly, it did this 200 times better than F0045(S) and was non-toxic, suggesting both efficacy and safety made this an impressive candidate for a flu-thwarting drug.
But wait, there's more. Using 6(R), the researchers then tweaked the 'recipe' for what they call compound 7 – a molecule with even greater antiviral power.
“This is the most potent small-molecule hemagglutinin inhibitor developed to date,” said corresponding author Seiya Kitamura, who worked on the project at Scripps Research and is now an assistant professor at the Albert Einstein College of Medicine.
The researchers are now working on optomizing their 'silver bullet' virus inhibitor, compound 7, which they'll then test on animal influenza A models.
“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,” Kitamura added.
The team is also looking at using a similar method to find a target for other strains of the virus, including H5N1 – what we most commonly know as avian influenza, which has the potential to pose a huge threat to humans if it becomes easily transmissible.
The research was published in the journal The Proceedings of the National Academy of Sciences
Source: Scripps Research institute
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May 22, 2024 at 01:48PM
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A world without flu: Long-lasting drug blocks Influenza A - New Atlas
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