Influenza A virus has caused pandemics over the last century. Symptoms of the infection includes cough, runny nose, muscle ache, headache and fever . Influenza infection can range from mild cases to life threatening cases and even death. Infection of the disease not only threatens life but also affects economic progress. There is even the likeliness of a direct infection of humans by avian viruses, as evidenced by the emergence of highly pathogenic avian influenza viruses of the H5N1 subtype that were capable to infect and kill humans . The Southeast Asia has been termed as the epicentre for influenza pandemics, and Philippines, being on this region is at high risk to future influenza pandemics.
The influenza virus belongs to orthomyxoviridae family. Virus strains causing pandemics could either be of avian or swine origin. The latest pandemic recorded in 2009 was induced by a novel H1N1 of swine origin . Influenza A is classified based on its hemagglutinin (HA) and neuraminidase (NA). 17 subtypes for HA (H1 to H17) and 10 for NA (N1 to N10). A novel subtype can occur upon introduction of an influenza virus in current global pandemic . This increases the threat caused by the virus.
Three main targets for influenza virus have been identified: NA, HA and the M2 proton channel. These targets are important for virus replication and proliferation. Hemagglutinin acts as an anchor attaching the virus to the sialic acid present on the target cell’s surface and signal triggers internalization of the virus to the cell. The M2 proton channel maintains pH virus’ pH and plays an important role in its uncoating. Neuraminidase, an enzyme which cleaves α-2,3 or α-2,6 sialic acid of the host cell membrane, is responsible for releasing the virus from the cell. [5,6].
Oseltamivir (Tamiflu, Roche) and zanamivir (Relenza, GlaxoSmithKline). Hemagglutinin binds to the sialic acid glycoconjugate of the host cell allowing the virus to enter the plasma membrane where the virus uncoats and replicates. Neuraminidase allows the release of the newly formed virion from the infected cell by cleaving the sialic acid . Oseltamivir and zanamivir act as inhibitor, blocking the active site of the neuraminidase preventing the release of newly synthesized virion. Zanamivir was the first small-molecule drug to be developed by structure-based rational drug design . It is administered as an oral inhalant. Structural improvement resulted to the formation of oseltamivir. It is administered as the prodrug oseltamivir phosphate (Tamiflu) which is converted to oseltamivir carboxylate, the active form, by the action of hepatic esterases . Resistance to oseltamivir occurs via H275Y (also known as H274Y) mutation of NA, a replacement of a single histidine with a tyrosine. This change in amino acid interferes with the drugs ability to bind with the NA. Fortunately, such virus are still susceptible to zanamivir . However,...