Oseltamivir phosphate (Tamiflu) is the ethyl ester prodrug of oseltamivir carboxylate, an analogue of neur-aminic (sialic) acid that is a reversible competitive antagonist of influenza A and B neuraminidase. Neuraminidase, like hemagglutinin, is a viral surface glyco-protein that interacts with host cell receptors containing terminal neuraminic acid residues. The binding of hemagglutinin to its cellular receptors initiates viral penetration and promotes the fusion of the viral envelope to the plasma membrane. Neuraminidase then destroys these hemagglutinin receptors by breaking the bond between the terminal neuraminic acid residue and its adjacent oligosaccharide. The cleavage of hemagglutinin receptors is required for the release of progeny virus from the host cell. It also facilitates the spread of infection by allowing viral particles to penetrate the neuraminic acid-rich respiratory mucus and by preventing the clumping of virus that results from the binding of hemagglutinins to neuraminic acid residues on neighboring viral particles. Inhibition of neuraminidase activity prevents the release of progeny virus and inhibits viral spread. The active site of neuraminidase is highly conserved in influenza A and B viruses; thus, oseltamivir and other neuraminidase inhibitors (e.g., zanamivir) are effective against a variety of influenza strains.
Influenza virus resistant to oseltamivir has not been found in naturally acquired isolates but has been isolated from influenza patients who have undergone treatment with this drug. These resistant strains contain mutations in the active site of neuraminidase and are generally less virulent and infective than nonresistant virus. In vitro passage of influenza virus in the presence of oseltamivir carboxylate can produce mutations in hemagglutinin that decrease the overall dependence of viral replication on neuraminidase; however, the clinical relevance of this resistance mechanism is unknown.
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