New bird flu drug promises to beat the problem of resistance

A new kind of drug to fight bird flu that will not suffer from the same kind of resistance problems as current treatments should begin clinical trials within the next three years, thanks to a new research grant.

Dr Andrew Watts from the University of Bath (UK) and Dr Jennifer McKimm-Breschkin from CSIRO (Australia) have been awarded over £408,000 from the Medical Research Council (MRC) to develop a new class of inhibitor they have discovered into a new kind of antiviral influenza drug.

The search for an alternative flu drug has become all the more pressing as the full extent of resistance – the ability of the influenza virus to withstand drug treatments - becomes more widely understood.

Both Tamiflu and Relenza, the two drugs currently being stockpiled by governments in preparation for a global outbreak of bird flu, are inherently susceptible to resistance because of the way they work.

The first major warning of the practical implications of this came with research published in the New England Journal of Medicine in December 2005.

This reported that from a group of eight Vietnamese bird flu patients treated with Tamiflu (also known as Oseltamivir), two patients showed initial signs of recovery before eventually dying. This suggests that the influenza virus was able to rapidly develop resistance to the drug.

In another study in Japan, the virus developed resistance in one in six children treated with Tamiflu for ordinary forms of flu.

Although acting upon the same target on the influenza virus as existing treatments, the new drug molecules being developed are specific for a part of the virus that is unable to mutate (change), which means it should be impossible for the influenza virus to develop resistance.

"Tamiflu and Relenza remain our best lines of defence against a flu pandemic, but we need to be working on better alternatives that do not suffer the same inherent resistance problems," said Dr Andrew Watts from the Department of Pharmacy and Pharmacology at the University of Bath.

"We are still in the very early stages of the development of this class of molecules into a drug, but the initial tests, and what we already know about how it works, are very, very encouraging.

"By the time the influenza virus becomes fully resistant to the drugs currently in use, we should have this as a viable alternative."

Dr McKimm-Breschkin is also very optimistic about the new project.

"We are aiming to produce a likely drug candidate within the three year period," she said.

"However, given the long period of time it takes to properly trial and evaluate a new anti-viral drug, it could be up to fifteen years before we see the resulting treatment on the shelves."

Whilst Dr Watts will be making the molecules at the University of Bath, the initial trials on the influenza virus will be carried out by Dr Mckimm-Breschkin at CSIRO in Melbourne.

CSIRO was instrumental in developing the world's first anti-flu drug effective against all strains of flu. Dr McKimm-Breschkin was part of the team that developed Relenza which remains one of only two drugs considered effective treatments against avian influenza, and she has also carried out much of the research on influenza drug resistance.

How it works

The flu virus is like a football coated with two different types of enzymes. These are proteins which carry out specific jobs for the virus.

The first of these proteins, haemagglutinin (H), helps the virus to invade cells in the throat whilst the second, neuraminidase (N), allows the new virus particles to chop their way off the surface of an infected cell so that they can spread to infect other cells.

(Differences in the H and N proteins allow scientists to distinguish between the different types of influenza virus. For instance, the current strain of avian influenza circulating is H5N1)

Relenza, Tamiflu and the new class of molecules being developed, are known as neuraminidase inhibitors because they prevent the neuraminidase enzyme from working properly.

The drugs can do this because their molecular structure closely resembles the molecules the enzyme normally attaches to on the infected cell, except the drug molecules bind much tighter to the neuraminidase.

Rather than interacting with the molecules on the surface of the infected cell, the neuraminidase enzyme binds to the drug instead. The drug physically gets in the way and inhibits the action of the enzyme.

This stops the virus from spreading to new cells and helps to reduce the severity and duration of flu so that the body's own defence mechanisms, together with other medical interventions, can help aid recovery.

However, the influenza virus can develop resistance to the drugs by mutating, or changing, parts of its surface that Tamiflu and Relenza absolutely need to achieve their strong binding to the neuraminidase. When this happens, the neuraminidase is able to escape from the drug and continue its job.

The new class of molecule being developed by the University of Bath and CSIRO researchers blocks the action of the neuraminidase in a very different manner, by undergoing a chemical reaction with protein. Furthermore, this chemical reaction only takes place at one specific part of the neuraminidase, a part that is essential for the neuraminidase to carry out its natural job.

This process stops the neuraminidase enzyme in its tracks, and makes it impossible for the virus to develop resistance to the new molecule.

The researchers are currently narrowing-down the class of molecules they have discovered to identify the best candidate for developing a drug. They will then need to refine the delivery mechanisms and begin trials that will ensure its efficacy in patients.

Source : University of Bath