By good fortune, scientists at The Scripps Research Institute say they’ve made a significant discovery that could lead to better flu treatments.

The scientists found a small molecule that blocks a vulnerable site on many Type A influenza viruses that is required for infection. If this discovery is confirmed, the scientists say it could guide development of a new class of flu drugs.

The discovery, published Monday, comes at a time when better flu drugs are badly needed. Seasonal vaccines offer only modest protection. Antiviral flu drugs are losing effectiveness. This flu season was one of the more severe ones, with deaths in San Diego County alone reaching 319 as of March 24.

However, the study is just the first step of a lengthy process that may or may not lead to an effective treatment. Years lie ahead, with more lab testing and probably animal experiments before any drugs can be tested in people. And success is far from guaranteed.


The study’s significance is that it suddenly opens up a new area of exploration into a long-held dream of developing potent small-molecule flu drugs. Moreover, it’s the second in a month from San Diego scientists reporting a novel method of developing such flu drugs.

Small molecules are preferred as drugs, because they can be manufactured inexpensively and taken orally. Large-molecule drugs are generally trickier to make and often can’t be taken by mouth. And flu viruses are relatively huge, plus most of their surface is highly mutable. That means finding the right place to block a vulnerable site that doesn’t change is effectively a needle-in-a-haystack challenge.

Meanwhile, existing small molecule drugs such as Tamiflu are only partially effective. And recent research suggests that the effectiveness of such drugs has been overstated. (Flu vaccines are made of large molecules, but their main problem is limited effectiveness, not cost).

The lastest study was published in the Proceedings of the National Academy of Sciences. Ian Wilson, a longtime vaccine researcher, was the senior author. Rameshwar Kadam, also of Scripps Research, was first author.


In an unrelated study published in March, scientists from UC San Diego reported producing another potential small molecule that in theory could provide virtually universal flu protection. This molecule stops flu viruses from reproducing inside an infected cell. But this research also requires further development before it can be tested in people.

The new study found that a commonly used laboratory chemical known as CHES blocks infection. Researchers discovered its flu-blocking property by accident, while preparing crystallized forms of the H5N1 virus for imaging with X-rays.

They delved into the viral structure and the molecule’s chemistry to deduce how this happened. Ultimately, they arrived at an atomic-level description of how the molecules interact.

CHES fits precisely into a shallow pocket on the viral surface, the needle in the haystack. This area docks with protrusions of carbohydrate molecules called sialic acids that bristle from cells. This docking is required for infection.


Researchers have sought to to stop this docking with carbohydrate-based decoys that look like sialic acids. But this effort has failed, because the sialic acid receptor only binds weakly. A tight attachment is needed to deactivate the virus.

It is for that reason, the study states, that it’s important to explore non-carbohydrate small molecules as potential drugs.

With that in mind, the researchers noticed that X-rays of their crystallized virus samples showed something inside the receptor binding site. They determined it was CHES, a non-carbohydrate small molecule.

And most importantly, the molecule did not intrude into other areas around the receptor that are highly variable. This means that the molecule should be able to fit into the receptor pocket even as the virus mutates.


The study can be found online at j.mp/fluches.


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