Flu-fighters: new influenza agent found

21 February 2013
Posted by Chris Smith.

A potent new flu drug has been discovered by scientists in Canada. It works by deactivating an enzyme called neuraminidase. 3D Model of an influenza virus particle.This is present on the surfaces of flu virus particles where it has the role of breaking down a sticky substance on cells called sialic acid, which would otherwise prevent the virus from spreading to surrounding uninfected cells.

Drugs called neuraminidase inhibitors, famously Tamiflu (oseltamivir), already exist to target this system.

They work by binding tightly to the same part of the enzyme that recognises and cuts sialic acid, preventing the enzyme from working.

But their use is limited because resistant strains of flu appear quite quickly when these agents are used, since the virus can alter the shape of its neuraminidase enzyme to prevent the drug from binding.

Now University of British Columbia scientist Stephen Withers has taken an alternative approach. He reasoned that if a drug is almost identical in shape to the molecule the enzyme is supposed to work on, then it is much more difficult for resistance to develop because a change in shape to avoid binding the drug would also prevent the normal molecule binding too.

So Withers and his team have come up with a family of molecules based on a chemical called difluorosialic acid (DFSA).

This closely resembles the normal sialic acid recognised by neuraminidase, but when the 'flu enzyme acts on it, the resulting chemical change produces a molecule that binds and blocks the enzyme, deactivating it for up to 100 hours.

In tests on different strains of flu, the new agents repeatedly outperformed Tamiflu and its competitor Ralenza (zanamivir), including against strains of the virus that were already resistant.

The new compounds also blocked the growth of flu in cells infected in the dish, critically without producing any signs of toxicity in the cells themselves, and tests on flu-infected mice protected all of the animals from what was otherwise a lethal dose.

As the scientists say in their paper in Science, the similarity of these new drug molecules to the molecules that are already naturally present in the body makes them "attractive antiviral candidates"...

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