NIMR scientists discover H5N1’s Achilles heel
National Institute for Medical research scientists have discovered subtle variations in the structure of the bird flu virus H5N1, a finding that could lead to more effective anti-flu drugs.
All flu viruses have the proteins haemagglutinin and neuraminidase on their coats – the H and the N. Neuraminidase comes in nine forms. It allows the virus to be released from infected cells and infect new ones.
Today the drug oseltamivir, better known as Tamiflu, which is taken by mouth, is the best defence against the often lethal H5N1 strain. The closely related zanamivir (Relenza) is also effective, but it must be inhaled — a problem when the lungs are damaged by the flu.
Both dugs are designed to block neuraminidase, but they are based on the structures of the N2 and N9 forms of the enzyme, as these were the only ones available when these drugs were created. Although they are effective against flu viruses with other types of neuraminidase, the assumption that this was because the 'active site' — the part of the enzyme that cuts viruses free from cells and also where the drugs bind — must be identical in all of the types has been disproved by this latest research into the structure of N1.
John Skehel and his colleagues used X-ray crystallography to determine the structures of three other types of neuraminidase: N1, N4 and N8. They found that the three-dimensional structures of the active site differed from those in N2 and N9. When N1, N4 and N8 bind their normal targets, a small cavity next to the active site closes up. These findings could lead to real breakthroughs in drug development, potentially allowing for sub-type specific drugs and combating drug-resistance.
Journal abstract available at Nature
