16/08/06

Bird flu protein’s ‘pocket’ could inspire better drugs

Simplified depiction of a flu virus's N-protein, neuraminidase Copyright: NASA

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Researchers have discovered a detail of the H5N1 bird flu virus’s structure that could be exploited to make new, targeted influenza drugs.


Their study, published online by Nature today (16 August), also warns of ways in which H5N1 could mutate and become resistant to existing drugs.


John Skehel of the UK National Institute for Medical Research and his colleagues characterised a key protein on the surface of H5N1.


Influenza strains such as H5N1 are named after differences in the structure of two proteins, known as H and N. The N protein (neuraminidase) allows viruses that have replicated inside an infected cell to leave the cell and infect others.


Flu drugs Tamiflu and Relenza, which work by inhibiting this protein, were developed using the structure of the N2 and N9 forms of neuraminidase. The N2 form is found in some of the flu viruses that trigger seasonal flu.


It was assumed, until now, that because these drugs were effective against H5N1 and H1N1 viruses, the N1 protein had a similar structure.


Skehel and colleagues show that this is not the case.


In the N1 form of the protein, a small segment called the 150-loop is inverted, creating a hollow pocket that does not exist in the N2 and N9 proteins.


This means that even though the classic flu drugs are effective against N1 flu viruses, the previously unknown ‘pocket’ could be exploited to design a drug that would be even more effective against H5N1-like viruses.


“This is a very interesting and important scientific finding that also has practical implications,” says Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases.


When the researchers looked at how existing drugs interacted with the N1 protein, they found that, in the presence of neuraminidase inhibitors, the loop changed its conformation to one similar to that in the N2 and N9 proteins.


This, according to Ming Luo, a microbiologist at University of Alabama in the United States, suggests that the researchers who designed the drugs struck lucky.


If the change to the 150-loop did not occur in the presence of the drugs, any virus with the N1 form of the protein — such as H5N1— would be resistant.


Luo, who comments on the study in Nature this week, also points out that the difference between the ‘inwards’ and ‘outwards’ 150-loops must lie outside the protein’s ‘active site’.


This is the part of the protein that drugs attach to, and which researchers usually target when developing new drugs.


Skehel’s team’s discovery, writes Luo, means that researchers should pay close attention to genetic changes in flu viruses that alter other parts of the N protein’s structure.


“Such changes might result in a mutant virus that is resistant to current drugs,” he warns.


Link to full paper in Nature


Link to accompanying commentary by Luo

Reference: Nature doi: 10.1038/nature05114 (2006)