Zanamivir
Zanamivir is a neuraminidase inhibitor used in the treatment of and prophylaxis of both influenza A and influenza B. Zanamivir was the first neuraminidase inhibitor commercially developed. It is currently marketed by GlaxoSmithKline under the trade name Relenza®.
Development
Zanamivir was developed by Australian researchers at Monash University, and later the Australian biotechnology company Biota Holdings as part of their ongoing program to develop antiviral agents through rational drug design. An outline of the successful rational design strategy used was published in a paper in Nature (von Itzstein et al., 1993).
The strategy relied on the availability of the crystal structure of influenza neuraminidase which was achieved by x-ray crystallography. It was 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 (Meindl et al., 1974). Using the crystal structure of neuraminidase and DANA as a starting point, the researchers employed a computer-aided process to attempt to design a molecule which better fitted (and therefore inhibited) the active site of neuraminidase. Zanamivir, a transition-state analogue inhibitor of neuraminidase, was the result.
Limitations
Whilst zanamivir proved to be a potent and effective inhibitor of influenza neuraminidase and inhibitor of influenza virus replication in vitro and in vivo, this didn't necessarily translate into a successful clinical treatment for influenza. In clinical trials it was found that zanamivir was able to reduce the time to symptom resolution by 1.5 days provided therapy was started within 48 hours of the onset of symptoms.
A further limitation concerns the poor oral bioavailability of zanamivir. This meant that oral dosing was impossible limiting dosing to the parenteral routes. Zanamivir, therefore, is administered by inhalation - a route that was chosen for patient compliance with therapy. But even this route of administration is not acceptable to many in the community.
A troubled commercial venture
Biota, only being a small company, was not able to bring the drug to market by itself. Consequently, it was licensed to GlaxoWellcome (now GlaxoSmithKline) to market internationally as Relenza, delivered via their proprietary Diskhaler inhalation device.
A combination of factors have resulted in the limited commercial success of zanamivir. The relatively small effect on the timecourse of influenza symptoms, the inhalation dosage form, and high expense have all contributed to the relatively poor sales of Relenza.
A prototype for others
Zanamivir was the first of the neuraminidase inhibitors. Despite the limited commercial success of this drug, the work and strategies employed in the development of zanamivir were important first-steps in the development of further members of this class including oseltamivir and the candidate drug RWJ-270201 (Phase I trials). As a result more effective and potent treatments for influenza may be developed in the future.
References
- Meindl, P., Bodo, G., Palese, P., Schulman, J., Tuppy, H. Inhibition of neuraminidase activity by derivatives of 2-deoxy-2,3-dehydro-N-acetyl-neuraminic acid. Virology 58, 457-463 (1974).
- von Itzstein M., Wu, W-Y., Kok, G.B., Pegg, M.S., Dyason, J.C., Jin, B., Phan, T.V., Smythe, M.L., White, H.F., Oliver, S.W., et al. Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature 363, 418-423 (1993).
