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Relenzaä : a rationally designed anti-influenza drug R.J. Fenton, BSc, PhD Relenzaä
(zanamivir, 4-guanidino-Neu5Ac2en) is first in its class of influenza specific neuraminidase inhibitors. Neuraminidase, a glycoprotein found on the surface of influenza virions, destroys sialic acid-containing receptors on infected cells and on progeny virions. This activity facilitates the elution of newly budded virus from the infected cell surface and thus contributes to the viral burden in the host. On the basis of the three-dimensional structure of neuraminidase and the structure of the enzyme-product complex, novel analogues of the product (sialic acid, Neu5Ac) were designed and were shown to be potent inhibitors of neuraminidase in vitro and in vivo. Relenzaä
is one of the most potent of the sialic acid analogues described to date. It is broadly inhibitory of all type A and B neuraminidases, interacting with strain-invariant amino acids inside the active site of the enzyme. Inhibition of neuraminidase translates into antiviral activity in tissue culture, in animal models of influenza and in both experimental and naturally acquired influenza in humans. To deliver Relenzaä
directly to the lungs of patients the agent has been formulated for inhalation using a modified Diskhalerä, which ensures high local concentrations and maximises inhibition of viral neuraminidase. Significant benefit has been shown in clinical trials, whilst demonstrating a safety profile equivalent to placebo. Relenzaä
is currently available for the treatment of influenza in Australia, New Zealand, the USA and most European member states. In addition, it is now available for prophylaxis in Switzerland, and has also been submitted for the prevention of influenza in European member states. |
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