H5N1's Achilles Heel?
The aggressive H5N1 virus was first isolated in China ten years ago. It spread to Southeast Asia in the winter of 2003/2004, reached Europe in the winter of 2005/2006, and reached Africa in 2006. Does the virus have a vulnerability to grab hold of to h alt its advance?
Europe has so far been largely spared from bird flu - but here, too, free-living birds and also breeding poultry died from the aggressive virus. In Germany, even cats and a marten became infected with the disease. The little creep doesn't stop at humans either: there are currently 238 infections and 139 human deaths from the bird flu virus reported worldwide.
Things will get really serious when the virus gains the ability to jump from person to person – which it is not yet able to do. Should it come to that, a global pandemic would threaten. The development of the virus is monitored accordingly. At the same time, countermeasures are being worked on so that the virus is not helpless in an emergency.
Infected patients are currently given the only two available flu drugs, oseltamivir (Tamiflu) and zanamivir (Relenza). Both drugs paralyze the viral enzyme neuraminidase. This protein helps the virus get out of the cell it has multiplied in and reinfect other cells.
However, neuraminidase is not the same as neuraminidase: This protein is available in nine different variants from N1 to N9, which in turn are divided into two groups, namely group 1 with N1, N4, N5 and N8 and group 2 with N2, N3, N6, N7 and N9 are combined. Viruses attack humans with the two neuramindase subtypes N1 and N2.
N2 and N9-the only subtypes whose structure was known so far-served as templates for the development of oseltamivir and zanamivir. Fortunately, since these also work against the virus variant of the N1 subtype - which attacks humans - it is assumed that the point of attack for the drugs is identical for all variants of neuraminidase.
But, as is so often the case, the viruses defend themselves against the drugs: Resistant viruses have already emerged against Tamiflu. New drugs that also target H5N1 and the currently circulating human pathogenic virus of the H1N1 type are needed.
Therefore, John Skehel from the National Institute of Medical Research in London and his team analyzed the structure of subtype N1 neuraminidase. They found that their binding site for the flu drug is completely different from that of N2 and N9.
A specific piece of the amino acid chain that builds the protein, the so-called 150 loop, is located in the molecule in N1 in a completely different way than in N2 and N9. This creates an additional cavity at N1 in the binding site. Two other members of group 2 neuraminidases, N4 and N8, also have this additional cavity.
Because of this deviating structure, the flu drugs should actually not be able to bind to group 2 neuraminidases at all and therefore not have any effect. But the neuraminidase inhibitors simply adapt the binding site: the scientists were able to observe that the 150 loop simply flips over when oseltamivir binds, so that the binding site suddenly looks the same as in group 1 neuraminidases. This is probably why the drugs counteract it all neuraminidases.
The special cavity of the group 2 neuraminidases should become even more important in the future: According to the scientists, it can serve as a target for new flu drugs that are specifically directed against these subtypes. With tailor-made weapons against the bird flu virus, humans would be well armed against the threat of a pandemic.
