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Date of publication:2020/10/10 16:23:17

Influenza virus is one of the main human pathogens that cause respiratory diseases. It causes high morbidity and mortality through seasonal influenza and global pandemics. Vaccines and antiviral drugs can be used to prevent and treat influenza infections, respectively. Unfortunately, the RNA genome of influenza viruses will continue to mutate, and genome fragments may recombine to form new virus subtypes. Although vaccines are the most effective way to prevent influenza, due to changes in the spread of influenza viruses, vaccine formulations must be updated every year, and the production of influenza vaccines takes several months. If the prediction of the upcoming influenza virus strain is incorrect, the protection of the vaccine may be limited.

There have been several influenza pandemics in the past, such as the Spanish influenza caused by the H1N1 virus in 1918, the Asian influenza caused by the H2N2 virus in 1957, the Hong Kong influenza caused by the H3N2 virus in 1968, and the bird flu caused by the H5N1 and H7N9 viruses respectively. And the swine flu caused by the H1N1 virus in 2009. The flu pandemic has claimed the lives of many people and caused huge economic losses in many countries. The universal flu vaccine is still elusive.

Timeline showing influenza pandemics caused by influenza A viruses
Timeline showing influenza pandemics caused by influenza A viruses, image source: https://jbiomedsci.biomedcentral.com/

Infection and propagation route of influenza virus

The life cycle of influenza virus is a complex biological process, which can be divided into the following steps (Figure 2): (i) virion attaches to the cell surface (receptor binding); (ii) internalization of the virus into the cell (endocytosis); (iii) viral ribonucleoprotein (vRNP) decapsidation, cytoplasmic transport and nuclear import; (iv) transcription and replication of viral RNA; (v) nuclear export and protein synthesis; (vi) viral progeny assembly, budding and release from the cell membrane. All these steps in the life cycle of an influenza virus are essential for its virulence, replication and transmission. The development of a small molecule inhibitor that can prevent any of these steps can lead to potentially effective strategies to control and prevent influenza infection.

Schematic representation of the life cycle of influenza virus
Schematic representation of the life cycle of the influenza virus, 
image source: https://jbiomedsci.biomedcentral.com/

Approved anti-influenza drugs

There are several approved influenza antiviral drugs, including M2 ion channel blockers, neuraminidase inhibitors, and an endonuclease inhibitor.

Anti-Influenza Drugs
M2 ion channel inhibitors  Neuraminidase inhibitors Endonuclease inhibitor
Amantadine Oseltamivir  Baloxavir marboxil
Rimantadine Zanamivir   

Chemical structures of currently available licensed anti-flu drugs.
Chemical structures of currently available licensed anti-flu drugs, image source: https://jbiomedsci.biomedcentral.com/

The two M2 ion channel inhibitors, amantadine, and rimantadine historically have been approved for treatment and prevention of influenza A virus infection. However, the efficacy of M2 ion channel inhibitors is limited to influenza A because influenza B viruses lack M2 protein. In addition, almost all influenza strains have developed high resistance against both amantadine and rimantadine. The M2 ion channel inhibitors are now largely discontinued and replaced by NA inhibitors.

There are four FDA-approved influenza antiviral drugs recommended by CDC for use against recently circulating influenza viruses.

  • ● Zanamivir (Relenza™; GlaxoSmithKline, 1999)
  • ​ Oseltamivir phosphate (Tamiflu™; Hoffmann-La Roche, 1999) 
  • ​ Peramivir (Rapivab™; BioCryst Pharm, 2014).
  • ​ Baloxavir marboxil (Xofluza; Roche, 2018)

Zanamivir is more effective than oseltamivir, but the oral bioavailability of zanamivir in humans is poor (<5%). This may be because zanamivir is a hydrophilic compound that is water soluble and readily eliminated through the renal system. Zanamivir is usually administered by intranasal or dry powder inhalation. After inhaling dry powder, about 7-21% is deposited in the lower respiratory tract, and the rest is deposited in the oropharynx. To prevent influenza, the recommended dose of zanamivir is 20 mg/50 kg/ day inhaled twice a day for adults (half dose at each inhalation). Zanamivir has fewer adverse drug reactions than oseltamivir because zanamivir has a glycerol side chain, which is similar to the chemical structure of sialic acid, a natural sialic acid substrate.

Tamiflu is a phosphate salt of oseltamivir, a popular oral anti-flu drug. It is well absorbed and rapidly cleaved by endogenous esterases in the gastrointestinal tract, liver and blood to give oseltamivir carboxylate. To treat influenza, the recommended dose of oseltamivir for adults is 75  mg twice a day for 5 days. If Tamiflu is used 48 hours after influenza infection, the effect is poor. The preventive dose is usually 75 mg once a day for at least 10 days or up to 6 weeks during a community outbreak. Compared with zanamivir, oseltamivir has more adverse reactions and tends to induce drug-resistant virus strains.

Peramivir has low oral bioavailability. During influenza treatment, a single intravenous drip of 300 mg should be administered within 15 minutes. Peramivir is an effective inhibitor against influenza A and B viruses with good safety. Peramivir can be used to treat patients who cannot use oral medications or who are not sensitive to oseltamivir and zanamivir.

XOFLUZA is a first-in-class, single-dose, oral antiviral medicine that blocks an enzyme within the flu virus, stopping viral replication early in the influenza lifecycle.  It is a tablet taken as a single dose by mouth within 48 hours of flu symptoms. The dose depends on the patient's weight.

Huateng Pharma is known worldwide for a variety of pharmaceutical intermediates used in research and development. Recognized for purity and quality, our products and brands are backed by technical and sales teams dedicated to providing you the best service possible. We can provide anti-influenza drug intermediates such as Baloxavir Marboxil intermediates and Oseltamivir intermediates for your research. We can make scale-up production with capacities varying from gram to kilograms and multi tons.

Related Articles:
[1] Baloxavir Marboxil for Uncomplicated Influenza: Mechanism of Action & Side Effects
[2] The Development History of Tamiflu Oseltamivir
[3] What Are Viruses And What Kills Viruses in the Body?
[4] Xofluza vs. Tamiflu: Differences Between The Antiviral Flu Treatments
[5] The Basic Things We Have To Know About Influenza Virus