Influenza A(IC50= 0.95 nM);Influenza B(IC50= 2.7 nM)
Zanamivir targets the influenza virus neuraminidase (NA) glycoprotein, which is expressed on the surface of the viral envelope. By binding to the conserved active site of the neuraminidase enzyme, zanamivir prevents the cleavage of sialic acid residues from the host cell surface receptors. This inhibition blocks the release of newly formed virions from the infected host cell, preventing the spread of the virus to other cells and effectively halting the progression of the infection.

Zanamivir (GR-121167X; GG-167; Relenza) interacts with a group of amino acids in the active site of neuraminidase, which are conserved in all influenza A and B strains.By inhibiting neuraminidase's ability to cleave sialic acid on cell receptors, zanamivir stops the release and dissemination of newly formed virions[2].
Zanamivir is a potent inhibitor of influenza virus neuraminidase, with IC₅₀ values of 0.95 nM for influenza A and 2.7 nM for influenza B. It is selective for the viral neuraminidase over its human lysosomal equivalent, which contributes to its favorable safety profile. Zanamivir also significantly inhibits human sialidases NEU3 and NEU2 in the micromolar range (Ki 3.7 and 12.9 µM, respectively), which may account for some of its rare side effects.

Zanamivir has a poor bioavailability in oral administration, with only 4–17% of the agent. Because of its strong hydrophilic nature, which restricts its transport across the intestinal epithelium, oral delivery of zanamivir has proven to be problematic. When combined with zanamivir, permeability enhancers like sodium cholate and hydroxypropyl β-cyclodextrin can improve intestinal permeability[3].
Zanamivir is clinically effective in vivo for the treatment of uncomplicated acute illness due to influenza A and B virus in adults and pediatric patients. It has also been shown to be effective for the prevention of influenza. The drug significantly reduces the duration of influenza symptoms and the severity of the illness when administered within 48 hours of symptom onset. Clinical studies have demonstrated its efficacy in shortening the time to alleviation of major symptoms of influenza.

Non-cellular enzyme assays for zanamivir involve assessing its inhibition of influenza virus neuraminidase activity using purified viral enzyme preparations. The enzyme is incubated with a fluorogenic substrate (e.g., 2'-(4-methylumbelliferyl)-α-D-N-acetylneuraminic acid, MUNANA) in the presence of varying concentrations of zanamivir. The cleavage of the substrate releases a fluorescent product, which is measured using a fluorescence plate reader. IC₅₀ values are determined from dose-response curves by fitting the inhibition data to a non-linear regression model.

In vitro cellular assays for zanamivir are typically conducted using Madin-Darby canine kidney (MDCK) cells infected with influenza virus. Cells are seeded in 96-well plates and infected with a standardized amount of virus in the presence of varying concentrations of zanamivir. After incubation for a defined period (e.g., 48-72 hours), viral replication is quantified by measuring the cytopathic effect (CPE) using a colorimetric assay, or by plaque reduction assay. The EC₅₀ (effective concentration for 50% inhibition of viral replication) is determined from the dose-response curves.

Rats
Combinations Rats kept conscious are given IV-R (reference Zanamivir saline solution for intravenous injection) at a dose of 1 mg/kg.PO-SC (Zanamivir with SC for p.o.) and PO-C (Zanamivir control solution for p.o.) are given oral Zanamivir doses of 10 mg/kg. Before, at 0.5, 1, 2, 3, 4, 6, 8, and 24 hours after administration, blood samples are taken. Three rats from each group are sacrificed at each sampling point to remove the lungs following blood collection.After the rats' lungs are removed through a chest incision, the lungs are cleaned with saline. After that, the lungs are placed in an E-tube and kept in a freezer at -80°C until they are examined. After being centrifuged at 1,500 × g for 10 minutes, plasma samples are collected and kept at -20°C until analysis. Zanamivir is analyzed using the previously stated LC-MS/MS method in both plasma and lungs[3].
In vivo animal experiments with zanamivir are conducted in mouse and ferret models of influenza infection. Animals are infected intranasally with a lethal dose of influenza virus and then treated with zanamivir via intranasal administration, typically starting 24-48 hours post-infection. Efficacy is assessed by monitoring survival rates, weight loss, and clinical scores. Viral titers in the lungs are measured by plaque assay or qRT-PCR at various time points post-infection. The compound's ability to reduce viral load and improve survival outcomes is evaluated.

Absorption, Distribution and Excretion
The absolute bioavailability after oral administration is very low (2%). Bioavailability after oral inhalation is 4% to 17%. The drug is excreted unchanged in the urine and is completely eliminated within 24 hours of a single dose. Unabsorbed drug is excreted in the feces. Zanamivir is excreted unchanged via the kidneys. 2.5 - 10.9 L/h [after oral inhalation of 10 mg] 5.3 L/h [after a single intravenous injection of 4 mg or 2 mg in patients with normal renal function] 2.7 L/h [after a single intravenous injection of 4 mg or 2 mg in patients with mild to moderate renal impairment] 0.8 L/h [after a single intravenous injection of 4 mg or 2 mg in patients with severe renal impairment] Protein binding: Very low (<10%).
Oral inhalation of zanamivir results in systemic absorption, with an absorption rate of approximately 4% to 17%.
Elimination: Renal: Excreted unchanged in the urine, with a single dose eliminated within 24 hours. Total clearance ranges from 2.5 to 10.9 L/h. Fecal: Unabsorbed drug is excreted in the feces.
Time to Peak Effect: 72 hours.
For more complete data on the absorption, distribution, and excretion of zanamivir (7 metabolites), please visit the HSDB record page.

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Metabolism/Metabolites
Unmetabolized
Unmetabolized.

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Biological Half-Life
2.5–5.1 hours
The serum half-life of zanamivir after oral inhalation administration is 2.5 to 5.1 hours.
Zanamivir has a molecular weight of 332.31 and a molecular formula of C₁₂H₂₀N₄O₇. It is a solid at room temperature with a melting point of 274-277°C and is soluble in water. Following oral inhalation, zanamivir is poorly absorbed systemically, with approximately 4-17% of the dose reaching the systemic circulation. The drug is primarily concentrated in the respiratory tract, where it exerts its antiviral effect, and is excreted unchanged in the urine.

Hepatotoxicity
In randomized controlled trials, 2% to 3% of patients receiving zanamivir experienced elevated ALT or AST levels more than twice the upper limit of normal, but the incidence was similar in the placebo group. Despite the widespread use of zanamivir, there is little evidence that inhaled zanamivir causes liver injury, whether asymptomatic elevations in serum enzymes or clinically apparent liver disease. In a preliminary study of intravenous zanamivir for severe influenza, approximately 10% of patients reported elevated serum enzymes, occasionally accompanied by jaundice, but the relationship between zanamivir and potentially severe viral infection remains unclear. Probability score: E (unlikely a cause of clinically apparent liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation There is currently no information regarding the use of zanamivir during lactation. One group of authors estimated that if the mother inhaled a 10 mg dose of the drug, a fully breastfed 5 kg infant would receive approximately 0.075 mg of the drug daily from breast milk, less than 1% of the dose for older children. Furthermore, due to poor oral absorption of zanamivir, it is unlikely to reach clinically significant infant blood concentrations.
◉ Effects on breastfed infants
No relevant published information found as of the revision date.
◉ Effects on lactation and breast milk
No relevant published information found as of the revision date.

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Protein binding
Zanamivir has limited plasma protein binding (<10%).

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Interactions
Zanamivir is not a substrate of, nor does it affect, cytochrome P450 (CYP) isoenzymes (CYP1A1/2, 2A6, 2C9, 2C18, 2D6, 2E1, and 3A4) in human liver microsomes.
Zanamivir is generally well-tolerated, with the most common side effects being respiratory tract events such as cough, nasal irritation, and bronchospasm, particularly in patients with underlying respiratory disease. Rare but serious side effects include bronchospasm and anaphylaxis. The drug is classified as FDA Pregnancy Category C. Standard safety precautions should be followed when handling this compound, as it is intended for research and development use only, not for human therapeutic or diagnostic use.

[1]. Comparison of the activities of zanamivir, oseltamivir, and RWJ-270201 against clinical isolates ofinfluenza virus and neuraminidase inhibitor-resistant variants. Antimicrob Agents Chemother. 2001 Dec;45(12):3403-8.

[2]. Management of influenza virus infections with neuraminidase inhibitors: detection, incidence, and implications of drug resistance. Treat Respir Med. 2005;4(2):107-16.

[3]. Zanamivir oral delivery: enhanced plasma and lung bioavailability in rats. Biomol Ther (Seoul). 2013 Mar;21(2):161-9.

Zanamivir belongs to the guanidine class of compounds. It is an EC 3.2.1.18 (exo-α-sialidase) inhibitor and also an antiviral drug. It is a guanidino-neuraminidide that inhibits neuraminidase. Zanamivir is a neuraminidase inhibitor. Its mechanism of action is as a neuraminidase inhibitor. Zanamivir is an inhibitor of influenza virus neuraminidase and is administered via inhalation for the treatment and prevention of influenza A and B. At least in the case of inhalation administration, zanamivir has not been found to be associated with clinically significant liver injury. Zanamivir is a sialic acid analog neuraminidase inhibitor with antiviral activity. When administered via aerosol inhalation, zanamivir selectively binds to and inhibits the cleavage of sialic acid residues on the host cell membrane-binding glycoprotein receptor mediated by influenza A and B virus neuraminidase, thereby preventing the release of progeny viruses from the host cell surface and inhibiting further viral replication. A guanidino-neuraminidide that inhibits neuraminidase. Indications For the prevention and treatment of influenza A and B. FDA Label Dectova is indicated for the treatment of complicated and potentially life-threatening influenza A or B virus infections in adults and children (≥6 months) when: the patient's influenza virus is known or suspected to be resistant to other antiviral drugs besides zanamivir, and/or other antiviral drugs. Drugs used to treat influenza, including inhaled zanamivir, are not suitable for this patient. Dectova should be used according to official guidelines. Prevention and Treatment of Influenza Mechanism of Action Zanamivir's mechanism of action is by inhibiting influenza virus neuraminidase, which may alter the aggregation and release of viral particles. By binding to and inhibiting the neuraminidase protein, the drug prevents the influenza virus from escaping host cells and infecting other cells. Zanamivir is a potent, selective, competitive inhibitor of influenza virus neuraminidase, an enzyme essential for viral replication. Neuraminidase can cleave terminal sialic acid residues from glycoconjugates, thereby releasing the virus from infected cells, preventing the formation of viral aggregates after release from host cells, and potentially reducing the inactivation effect of respiratory mucus on the virus. Zanamivir is a selective inhibitor of neuraminidase in influenza A and B viruses, potentially altering viral particle aggregation and release.
Therapeutic Uses
Antiviral drug; enzyme inhibitor
Currently, the U.S. Centers for Disease Control and Prevention (CDC) recommends the use of oseltamivir or zanamivir for the treatment of swine influenza (H1N1) virus infection.
Drug: Antiviral drug; influenza virus neuraminidase inhibitor
Zanamivir is indicated for the treatment of uncomplicated acute illness caused by influenza A virus in adults and children aged 7 years and older, with symptoms present for no more than 2 days. Zanamivir must be started within 48 hours of the onset of flu symptoms. /U.S. product label contains/
For more complete data on the therapeutic uses of zanamivir (6 types), please visit the HSDB record page.

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Drug Warning
The swine flu (H1N1) virus contains a unique combination of gene segments that have not been previously reported in swine or human influenza viruses in the United States or elsewhere. The H1N1 virus is resistant to amantadine and ribavirin, but oseltamivir or zanamivir.
Some patients taking Relenza have reported bronchospasm and decreased lung function. Many (but not all) of these patients have underlying airway diseases such as asthma or chronic obstructive pulmonary disease. Due to the risk of serious adverse events and the lack of proven efficacy in this population, zanamivir is generally not recommended for the treatment of patients with underlying airway diseases. Some patients who experienced serious adverse events during zanamivir treatment have ultimately died, but causality is difficult to assess. Any patient experiencing bronchospasm or decreased respiratory function should discontinue zanamivir; immediate treatment and hospitalization may be required. Some patients without a history of lung disease may also experience respiratory abnormalities due to acute respiratory infections. These abnormalities may resemble adverse drug reactions or increase the patient's risk of developing adverse drug reactions. FDA Pregnancy Risk Category: B / No evidence of risk to humans. Although adverse reactions have been found in animal studies, adequately controlled studies in pregnant women have not shown an increased risk of fetal malformations; or, in the absence of adequate human studies, animal studies have shown no fetal risk. The possibility of fetal harm is small, but it still exists. / In 1–3% or more of adults and children 12 years and older, adverse reactions include diarrhea, nausea, vomiting, nasal symptoms, bronchitis, sinusitis, cough, ear, nose, and throat infections, headache, and dizziness. The incidence of no adverse reactions exceeds 3%. In children aged 5–12 years, the incidence of adverse reactions is up to 5%, including ear, nose, and throat infections, vomiting, nausea, and diarrhea. Some adverse reactions may be due to inhalation of lactose carriers. Bronchospasm and anaphylactoid reactions (including oropharyngeal edema and severe rash) have been reported. Unlike amantadine and ribavirin, neuraminidase inhibitors such as zanamivir do not appear to have adverse effects on the central nervous system. For more complete data on drug warnings for zanamivir (10 in total), please visit the HSDB record page.

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Pharmacodynamics
Zanamivir is an antiviral drug belonging to the neuraminidase inhibitor class, indicated for the treatment of uncomplicated acute illness caused by influenza A and B viruses in adults and children aged 7 years and older, with symptoms lasting no more than 2 days. Studies have shown that zanamivir also significantly inhibits human sialidases NEU3 and NEU2 at inhibitory concentrations in the micromolar range (Ki values of 3.7 ± 0.48 and 12.9 ± 0.07 μmol, respectively), which may be the cause of some rare side effects of zanamivir.
Zanamivir (CAS 139110-80-8) is a potent and selective inhibitor of influenza virus neuraminidase with IC₅₀ values of 0.95 nM (influenza A) and 2.7 nM (influenza B). It is marketed under the brand name Relenza and is administered via oral inhalation for the treatment of acute, uncomplicated influenza. The drug was developed through rational drug design and represents a milestone in structure-based drug discovery. Zanamivir is a valuable research tool for studying influenza virus biology and antiviral drug resistance mechanisms.

C12H20N4O7

332.313

332.133

C, 43.37; H, 6.07; N, 16.86; O, 33.70

139110-80-8

Zanamivir (hydrate)(5:1);171094-50-1

60855

White to off-white solid powder

1.8±0.1 g/cm3

256 °C

1.679

-4.13

7

8

6

23

518

5

O1C(C(=O)O[H])=C([H])[C@@]([H])([C@]([H])([C@]1([H])[C@@]([H])([C@@]([H])(C([H])([H])O[H])O[H])O[H])N([H])C(C([H])([H])[H])=O)/N=C(\N([H])[H])/N([H])[H]

ARAIBEBZBOPLMB-UFGQHTETSA-N

InChI=1S/C12H20N4O7/c1-4(18)15-8-5(16-12(13)14)2-7(11(21)22)23-10(8)9(20)6(19)3-17/h2,5-6,8-10,17,19-20H,3H2,1H3,(H,15,18)(H,21,22)(H4,13,14,16)/t5-,6+,8+,9+,10+/m0/s1

(2R,3R,4S)-3-acetamido-4-(diaminomethylideneamino)-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylic acid

Zanamivir; GR-121167X; GG167; GR121167X; GG-167; GR 121167X; GG 167; trade name Relenza.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : 33.33~36 mg/mL (~100.30 mM)
DMSO : ~66 mg/mL ( ~198.6 mM)

Solubility in Formulation 1: 9.09 mg/mL (27.35 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication (<60°C).

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 (Please use freshly prepared in vivo formulations for optimal results.)