Relenza (trade name) or Zanamivir (INN) is a neuraminidase inhibitor used in the treatment and prophylaxis of Influenzavirus A and Influenzavirus B. Zanamivir was the first neuraminidase inhibitor commercially developed. It is currently marketed by GlaxoSmithKline.
According to the Centers for Disease Control and Prevention (CDC), no flu, seasonal or pandemic, has shown any signs of resistance to zanamivir.
Zanamivir was discovered in 1989 by scientists led by Mark von Itzstein, at the Victorian College of Pharmacy, Monash University, in collaboration with the CSIRO and scientists at Glaxo, UK. Zanamivir was the first of the neuraminidase inhibitors. The discovery was funded initially by the Australian biotechnology company Biota and was part of Biota's ongoing program to develop antiviral agents through rational drug design. Its strategy relied on the availability of the structure of influenza neuraminidase, by X-ray crystallography. It was also known, as far back as 1974, that 2-deoxy-2,3-didehydro-''N''-acetylneuraminic acid (DANA), a sialic acid analogue, was an inhibitor of neuraminidase. Sialic acid (''N''-acetyl neuraminic acid, NANA), the substrate of neuraminidase, is itself a mild inhibitor of the enzyme, but the dehydrated derivative DANA, a transition-state analogue, is a better inhibitor.
Computational chemistry techniques were used to probe the active site of the enzyme, in an attempt to design derivatives of DANA that would bind tightly to the aminoacid residues of the catalytic site, and so would be potent and specific inhibitors of the enzyme. The software GRID from Molecular Discovery was used to determine energetically favourable interactions between various functional groups and residues in the catalytic site canyon. This showed there was a negatively charged zone in the neuraminidase active site that aligned with the C4 hydroxyl group of DANA. This hydroxyl was therefore replaced with a positively charged amino group; the 4-amino DANA was 100 times better an inhibitor than DANA, owing to the formation of a salt bridge with a conserved glutamic acid (119) in the active site. It was also noticed that Glu 119 was at the bottom of a conserved pocket in the active site just big enough to accommodate a more basic functional positively charged group, such as a guanidino group, which was also larger than the amino group. Zanamivir, a transition-state analogue inhibitor of neuraminidase, was the result.
Developments
Recently, the reported oseltamivir-resistance H5N1 virus neuraminidase still retaining susceptibility to zanamivir indicates that the structure of zanamivir has some advantages over oseltamivir in binding to the active pocket of H5N1 neuraminidase.
As a proven anti-influenza drug target, neuraminidase continues to be attractive for the development of new inhibitors. The crystal structure of H5N1 avian influenza neuraminidase (PDB code: 2HTY) provides the three-dimensional structural information and opportunity for finding new inhibitors in this regard, because the existing inhibitors, such as oseltamivir and zanamivir, were developed based on different structures of neuraminidase, such as subtypes N9, N2, and type B genus of influenza virus.
The drug is approved for use for the prevention and treatment of influenza in persons over the age of 7 in the United States, Canada, European Union and many other countries.
It is not recommended for people with respiratory problems and ailments.
Further Reading
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