Oseltamivir Tamiflu

Structural Formula

Structural Formula

= Carbon

Ball-and-Stick Model

Year of discovery: Early 1990s (by Gllead Sciences); Year of introduction: 1999 (Roche); Drug category: Neuraminidase inhibitor/antiviral; Main uses: For the treatment and prevention of influenza A and B viral infections; Related drugs: Zanamivir (Relenza), Peramivir.

Oseltamivir, a second-generation oral neuramidinase inhibitor, is widely used for the treatment and prevention of influenza A and B viral infections, including avian flu. Influenza is a serious respiratory illness that affects millions of people annually ("seasonal flu") and results in many deaths as well as an estimated $10 billion in lost productivity. The symptoms of flu and the common cold are similar, but flu symptoms are generally more severe. Older people and those with a weakened immune system are especially at risk to develop complications such as bronchitis and pneumonia which are the main causes of influenza-related deaths. In recent years a more virulent influenza A type virus, the avian flu, has emerged. Certain strains of the avian flu (e.g., H5N1) are able to infect humans and cause high mortality. Since the effective treatment of the various flu infections has traditionally been difficult due to the lack of potent antiviral drugs, the possibility of a catastrophic worldwide avian flu epidemic has arisen, as well as the urgent need for effective antiviral drugs. During the 1990s, the structure of the influenza neuramidinase enzyme that plays a crucial role in viral replication and infectivity was elucidated. In particular, neuramidinase cleaves sialic acid residues that connect the newly formed viruses to the surface of the host cell that it had infected. The synthesis of a large number of structural mimics of sialic acid led to the discovery of potent neuramidinase inhibitors that prevent the flu viruses from being released and limit the spread of the disease.

The first useful neuramidinase inhibitor, zanamivir (Relenza™), was discovered in 1989 using target-guided design. This drug, however, has poor bioavailability, can be administered only by inhalation and as a result it has seen limited clinical use.

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Sialic acid

Zanamivir (Relenza

The first orally active neuramidinase inhibitor, oseltamivir, was developed by C.U. Kim at Gilead Sciences in the early 1990s and marketed as Tamiflu by Roche.1,2 Oseltamivir itself is a prodrug that is activated by cleavage of the ethyl ester moiety (shown in blue above) to the carboxyl group (COOH). Currently oseltamivir is considered the only effective treatment for avian flu. The X-ray structure of oseltamivir carboxylate bound to neuramidinase (shown below) has been determined.3 Strong binding is the result of hydrogen bonding between Arg224 and Glu276 as well as hydrophobic interactions. However, resistant strains have already been reported. Resistant strains have mutations in certain amino acid residues (e.g., Arg292 to Lys and His274 to Tyr) that significantly reduce the binding affinity of oseltamivir to the enzyme.

1. J. Am. Chem. Soc. 1997, 119, 681-690; 2. Future Virology 2006, 1. 577-586; 3. Nature 2006. 443, 45-49 (2HT8); Refs.

^Hydrophobic pocket

Arg 152

Arg224

,Glu276:

His274

Glu119

Swine Influenza

Swine Influenza

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