Design of Neuraminidase Inhibitors against Influenza

The threat of a catastrophic outbreak of viral infection by the influenza virus is ever present, as has been recently experienced with avian flu, which it is feared could be transmitted to humans.89 Vaccines are only partially effective since the influenza virus has a very rapid rate of antigenic variation. Quite regularly, the virus undergoes a major antigenic transformation, resulting in a pandemic strain, such as the strain which killed more than 20 million people in 1918-1919. As a consequence, a pandemic can strike human and other populations, such as seal, horse, or fowl, at any time. Efficient prevention of a pandemic requires a simply administered drug that is effective against all types of influenza, has minimal side effects, and does not induce fast viral resistance. Up until 1998 only two compounds, amantidine and rimantidine, were used against influenza in the clinic. These compounds act by blocking the ion channel function of the virus protein M2.90 However, due to their side effects and the rapid emergence of resistant influenza strains, they were of only limited use and an alternative target, the influenza NA, has been explored. As a result of this research, there are now two drugs inhibiting NA approved for use in the clinic: zanamivir from GSK and oseltamivir from Hoffmann-La Roche and Gilead Sciences. A crucial breakthrough in this process was the determination of the crystal structure of influenza NA and its exploitation in structure-based drug design programs.

There are three types of influenza virus as classified by their serological cross-reactivity with viral matrix proteins and soluble nucleoprotein (A, B, and C). Only types A and B are known to cause severe diseases to humans. Type B is only found in humans, while type A occurs naturally in birds and mammals such as pigs and horses. Influenza, an orthomyxovirus, is a 100-nm lipid-enveloped virus. On the surface of the influenza virus there are two glycoproteins, hemagglutinin (HA) and NA, which appear as spikes protruding out of the viral envelope. There are between 50 and 100 NA spikes per virus.91 Electron microscopic images of the NA spikes reveal a mushroom-shaped molecule made up of a box-like head of about 80 x 80 x 40 A. It has a narrow centrally attached stalk (15A wide and 100 A long) which terminates in a hydrophobic knob anchored in the viral envelope.92 The spikes can be released by detergents and digested by pronase to release the NA 'heads,' which retain full antigenic and enzyme activity.93 NA was found to be a tetramer of molecular weight 240 kDa, which reduces to 200 kDa when treated with pronase.94 NA cleaves terminal sialic acid residues (compound 24) from glycoconjugates,95 promoting the release of newly formed virus particles from infected cells. Studies with a NA-deficient influenza virus have shown that the mutant virus is still infective but the budding virus particles form aggregates or remain bound to the infected cell surface,96 showing that NA is an attractive target against influenza.

Swine Influenza

Swine Influenza

SWINE INFLUENZA frightening you? CONCERNED about the health implications? Coughs and Sneezes Spread Diseases! Stop The Swine Flu from Spreading. Follow the advice to keep your family and friends safe from this virus and not become another victim. These simple cost free guidelines will help you to protect yourself from the swine flu.

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