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Zanamivir structure.svg
Systematic (IUPAC) name
(2R,3R,4S)-4-guanidino-3-(prop-1-en-2-ylamino)-2-((1R,2R)-1,2,3-trihydroxypropyl)-3,4-dihydro-2H-pyran-6-carboxylic acid
Clinical data
Trade names Relenza
AHFS/ monograph
Pregnancy cat. B1 (Au), C (US)
Legal status S4 (Au), POM (UK), ℞-only (U.S.)
Routes Inhalation
Pharmacokinetic data
Bioavailability 2% (oral)
Protein binding <10%
Metabolism Negligible
Half-life 2.5–5.1 hours
Excretion Renal
CAS number 139110-80-8 YesY
ATC code J05AH01
PubChem CID 60855
DrugBank DB00558
ChemSpider 54842 YesY
KEGG D00902 YesY
ChEBI CHEBI:50663 YesY
Synonyms 5-acetamido- 4-guanidino- 6-(1,2,3-trihydroxypropyl)- 5,6-dihydro- 4H-pyran- 2-carboxylic acid
Chemical data
Formula C12H20N4O7 
Mol. mass 332.31 g/mol
 YesY (what is this?)  (verify)

Zanamivir INN /zəˈnæmɨvɪər/ is a neuraminidase inhibitor used in the treatment and prophylaxis of influenza caused by influenza A and B viruses. Zanamivir was the first neuraminidase inhibitor commercially developed. It is currently marketed by GlaxoSmithKline under the trade name Relenza as a powder for oral inhalation.

Medical uses[edit]

Zanamivir is used for the treatment of infections caused by influenza A and influenza B viruses. Low to moderate evidence indicates it decreases the risk of one's getting influenza by 1% to 12% in those exposed.[1] In otherwise-healthy individuals, benefits overall appear to be small.[1] Whether it affects the risk of one's need to be hospitalized or the risk of death is not clear.[1] An independent analysis of its effects by the Cochrane collaboration was awaiting release of trial data as of 2012.[2] The evidence for a benefit in preventing influenza is weak in children, with concerns of publication bias in the literature.[3] As of 2009, no influenza has shown any signs of resistance.[4] Since then, genes expressing resistance to were found in patients infected with influenza A H7N9 and who were treated with corticosteroids.[5]

Adverse effects[edit]

Dosing is limited to the inhalation route. This restricts its usage, as treating asthmatics could induce bronchospasms.[6] The U.S. Food and Drug Administration (FDA) has issued a Public Health Advisory warning that it has received some reports of respiratory problems following inhalation of zanamivir by patients with underlying asthma or chronic obstructive pulmonary disease. The zanamivir package insert contains precautionary information regarding risk of bronchospasm in patients with respiratory disease.[7]

Zanamivir has not been known to cause toxic effects and has low systemic exposure to the human body.[8]

GlaxoSmithKline (GSK) and FDA notified healthcare professionals of a report of the death of a patient with influenza having received zanamivir inhalation powder, which was solubilized and administered by mechanical ventilation.[9]

Mechanism of action[edit]

Zanamivir works by binding to the active site of the neuraminidase protein, rendering the influenza virus unable to escape its host cell and infect others.[10] It is also an inhibitor of influenza virus replication in vitro and in vivo. In clinical trials, zanamivir was found to reduce the time-to-symptom resolution by 1.5 days if therapy was started within 48 hours of the onset of symptoms.

The bioavailability of zanamivir is 2%. After inhalation, zanamivir is concentrated in the lungs and oropharynx, where up to 15% of the dose is absorbed and excreted in urine.[11]


Zanamivir was discovered in 1989 by scientists led by Peter Malcolm Colman[12] and Joseph Varghese[13] at the CSIRO, in collaboration with the Victorian College of Pharmacy, Monash University, and scientists at Glaxo, UK. Zanamivir was the first of the neuraminidase inhibitors. The discovery was initially funded 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, is an inhibitor of neuraminidase.[14] 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 amino acid residues of the catalytic site, so would be potent and specific inhibitors of the enzyme. The GRID software by Molecular Discovery was used to determine energetically favourable interactions between various functional groups and residues in the catalytic site canyon. This investigation showed a negatively charged zone occurs in the neuraminidase active site that aligns with the C4 hydroxyl group of DANA. This hydroxyl is, therefore, replaced with a positively charged amino group; the 4-amino DANA was shown to be 100 times better as an inhibitor than DANA, owing to the formation of a salt bridge with a conserved glutamic acid (119) in the active site. Glu 119 was also noticed to be 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.[15] Zanamivir, a transition-state analogue inhibitor of neuraminidase, was the result.[16]

As Biota was a small company, it did not have the resources to bring zanamivir to market by itself. In 1990, zanamivir patent rights were licensed to Glaxo, now GlaxoSmithKline (GSK). In 1999, the product was approved for marketing in the US and subsequently has been registered by GSK in a total of 70 countries. [17] Zanamivir is delivered via Glaxo's proprietary Diskhaler inhalation device. The license agreement entitled Biota to receive a 7% royalty on Glaxo's sales of zanamivir.


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.[18][19][20]

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 and N2, and type B genus of influenza virus.

Commercial issues[edit]

Although zanamivir was the first neuraminidase inhibitor to the market, it had only a few months lead over the second entrant, oseltamivir (Tamiflu), with an oral tablet formulation.

According to the CDC, Tamiflu, zanamivir’s main competitor, is not as effective at treating the influenza viruses as zanamivir, especially in H1N1 seasonal flu. In fact, tests showed 99.6% of the tested strains of seasonal H1N1 flu and 0.5% of 2009 pandemic flu were resistant to Tamiflu, while no flu samples, seasonal or pandemic, showed any resistance to zanamivir.[4] [18][19]

When first marketed in the US in 1999/2000, zanamivir captured only 25% of the influenza antiviral market, despite a huge promotional campaign. By the end of that season, Tamiflu was outselling zanamivir 3:1. During that season, zanamivir experienced worldwide safety warnings involving the risk of bronchospasm and death. Glaxo then reduced the marketing of zanamivir, and Tamiflu's dominance increased. More than US$20 million worth of zanamivir sold by Glaxo in the first US season was returned to the company in the next two seasons because its sales to patients were far less than expected.

Biota commenced legal proceedings in 2004 alleging Glaxo's reduced marketing of zanamivir to be a breach of contract. Biota claimed about A$700 million from Glaxo. After Biota spent four years trying to progress its case, and incurring A$50 million in legal costs, the company abandoned the claim in July 2008, recovering only A$20 million, including legal costs following settlement at mediation. Biota had refused an earlier tactical offer from Glaxo of A$75 million plus legal costs.

In August 2006, Germany announced it would buy 1.7 million doses of zanamivir, as part of its preparation strategy against bird flu. "Germany's purchase shows that countries are starting to take a balanced view of influenza preparedness," said Simon Tucker, head of research at Melbourne-based Biota, where zanamivir was originally developed.[10]

In April 2009, many cases of swine flu (H1N1-type virus) were reported in US and Mexico. Zanamivir is one of only two drugs prescribed to treat it. A study published in June 2009 emphasized the urgent need for augmentation of oseltamivir stockpiles, with additional antiviral drugs including zanamivir, based on an evaluation of the performance of these drugs in the scenario that the 2009 H1N1 swine flu neuraminidase (NA) were to acquire the Tamiflu-resistance (His274Tyr) mutation, which is currently widespread in 99.6% of all tested seasonal H1N1 strains.[21]

In January 2011, GSK announced it would commence phase III trials for intravenous zanamivir in a study that will span 20 countries in the Northern and Southern Hemispheres.[22]

Legal status[edit]

The drug is approved for use for the prevention and treatment of influenza in those over the age of seven in the United States, Canada, the European Union, and many other countries. It is not recommended for people with respiratory problems and ailments.


Zanamivir synthesis.png
After Scheigetz et al.[23]


  1. ^ a b c Michiels, B; Van Puyenbroeck, K; Verhoeven, V; Vermeire, E; Coenen, S (2013). "The value of neuraminidase inhibitors for the prevention and treatment of seasonal influenza: a systematic review of systematic reviews.". PLoS ONE 8 (4): e60348. doi:10.1371/journal.pone.0060348. PMC 3614893. PMID 23565231. 
  2. ^ Jefferson, T; Jones, MA; Doshi, P; Del Mar, CB; Heneghan, CJ; Hama, R; Thompson, MJ (Jan 18, 2012). "Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children.". The Cochrane database of systematic reviews 1: CD008965. doi:10.1002/14651858.CD008965.pub3. PMID 22258996. 
  3. ^ Wang, K; Shun-Shin, M; Gill, P; Perera, R; Harnden, A (Apr 18, 2012). "Neuraminidase inhibitors for preventing and treating influenza in children (published trials only).". Cochrane database of systematic reviews (Online) 4: CD002744. doi:10.1002/14651858.CD002744.pub4. PMID 22513907. 
  4. ^ a b "2008-2009 Influenza Season Week 32 ending August 15, 2009". Flu Activity & Surveillance. Centers for Disease Control and Prevention (CDC). August 21, 2009. 
  5. ^
  6. ^ Hayden FG (December 2001). "Perspectives on antiviral use during pandemic influenza". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 356 (1416): 1877–84. doi:10.1098/rstb.2001.1007. PMC 1088564. PMID 11779387. 
  7. ^ "Safe and Appropriate Use of Influenza Drugs". Public Health Advisories (Drugs). U.S. Food and Drug Administration (FDA). April 30, 2009. Archived from the original on 2009-11-04. Retrieved 2009-11-11. 
  8. ^ Freund, B; Gravenstein, S; Elliott, M; Miller, I (1999 Oct). "Zanamivir: a review of clinical safety.". Drug safety : an international journal of medical toxicology and drug experience 21 (4): 267–81. PMID 10514019. 
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  10. ^ a b Cyranoski D (September 2005). "Threat of pandemic brings flu drug back to life". Nature Medicine 11 (9): 909. doi:10.1038/nm0905-909. PMID 16145557. 
  11. ^ Moscona A (September 2005). "Neuraminidase inhibitors for influenza". The New England Journal of Medicine 353 (13): 1363–73. doi:10.1056/NEJMra050740. PMID 16192481. 
  12. ^
  13. ^,+Joseph+Noozhumurry
  14. ^ Meindl P, Bodo G, Palese P, Schulman J, Tuppy H (April 1974). "Inhibition of neuraminidase activity by derivatives of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid". Virology 58 (2): 457–63. doi:10.1016/0042-6822(74)90080-4. PMID 4362431. 
  15. ^ Laver, Graeme (March 2007). "Flu drugs - pathway to discovery". Education in Chemistry. Retrieved 2009-11-11.  ISSN 0013-1350
  16. ^ von Itzstein M, Wu WY, Kok GB, et al. (June 1993). "Rational design of potent sialidase-based inhibitors of influenza virus replication". Nature 363 (6428): 418–23. doi:10.1038/363418a0. PMID 8502295. 
  17. ^ (GlaxoSmithKline News release, 2006).
  18. ^ a b Collins PJ, Haire LF, Lin YP, Liu J, Russell RJ, Walker PA, Skehel JJ, Martin SR, Hay AJ, Gamblin SJ. (2008). "Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants". Nature 453 (7199): 1258–61. doi:10.1038/nature06956. PMID 18480754. 
  19. ^ a b Garcia-Sosa AT, Sild S, Maran U. (2008). "Design of Multi-Binding-Site Inhibitors, Ligand Efficiency, and Consensus Screening of Avian Influenza H5N1 Wild-Type Neuraminidase and of the Oseltamivir-Resistant H274Y Variant". J. Chem. Inf. Model. 48 (10): 2074–2080. doi:10.1021/ci800242z. PMID 18847186. 
  20. ^ Du QS, Wang SQ, Chou KC (October 2007). "Analogue inhibitors by modifying oseltamivir based on the crystal neuraminidase structure for treating drug-resistant H5N1 virus". Biochemical and Biophysical Research Communications 362 (2): 525–31. doi:10.1016/j.bbrc.2007.08.025. PMID 17707775. 
  21. ^ Soundararajan V, Tharakaraman K, Raman R, Raguram S, Sasisekharan V, Sasisekharan R (June 2009). "Extrapolating from sequence--the 2009 H1N1 'swine' influenza virus". Nature Biotechnology 27 (6): 510–3. doi:10.1038/nbt0609-510. PMID 19513050. 
  22. ^ Hirschler, Ben (2011-01-19). "GSK tests intravenous flu drug vs Roche's Tamiflu". Reuters. 
  23. ^ Scheigetz, J.; Zamboni, R.; Bernstein, M. A.;Roy, B. (December 1995). "A syntheses of 4-a-guanidino-2-deoxy-2,3-didehydro n-acetylneuraminic acid". Organic Letters 27 (6): 637–644. doi:10.1021/ol901511x. Retrieved 2010-11-14. 

External links[edit]