What are Neuraminidase Inhibitors?

Neuraminidase inhibitors are antiviral drugs that are used to treat influenza infections. The influenza virus has two proteins on its surface. One of them is neuraminidase, an enzyme that frees newly-formed particles from the viral surface. This allows them to spread and infect other cells, after they have replicated. Two neuraminidase inhibitors are commercially available to treat influenza by blocking neuraminidase activity.

This type of enzyme is produced by a wide range of organisms. Neuraminidase breaks the bond of a sugar known as sialic acid, or neuramidin. On the influenza virus, the neuraminidase protrudes from the surface of the viral particle. Once the virus has reproduced, it remains connected to the host cell by the sialic acid until this sugar is cleaved.

Viral neuraminidase snips off the sugar that has attached the virus to the host, allowing it to bud off and spread the infection. It does this by adding a molecule of water to break the chemical bond of the sialic acid. This type of enzyme is known as a glycoside hydrolase.

There are nine different subtypes of neuraminidase, but only some occur in strains of influenza that affect humans. Along with hemagglutinin, the other protein on the viral surface, they help determine the infectivity of the virus. Some types of neuraminidase are more damaging to the host than others. They are used in the naming of the virus. For instance, the influenza virus responsible for the swine flu pandemic and seasonal influenza were designated H1N1, indicating that they had Type 1 hemagglutinin and neuraminidase.

The development of three-dimensional crystal structures for the viral neuraminidases was both an intellectual and practical achievement. This allowed researchers to use the structures as a model to develop neuraminidase inhibitors. Neuraminidase was a more attractive target for a drug than hemagglutinin, because it has a pocket in the molecule that serves as the active site for the enzyme.

Compounds were designed to bind in this pocket and prevent the enzyme from binding the cell’s sugar compound. With the neuraminidase inhibitors bound, the virus could no longer free itself from the cell. This effectively limits the replication of the virus.

The clinical results of these neuraminidase inhibitors were that the symptoms of the flu were delayed for 0.5 to 1.5 days. Since the virus can replicate in an hour, and produce many new virus particles, this was a significant finding. There are currently two such inhibitors on the market, oseltamivir, better known as Tamiflu®, and zanamivir, also known as Relenza®. These drugs are most effective when taken within 48 hours of the development of symptoms.

Both of these neuraminidase inhibitors act against influenzas A and B. There are different levels of resistance with the two drugs among some of the flu strains. The seasonal H1N1 virus displays a high level of resistance to Tamiflu®, but only a small degree of resistance is shown by the swine flu H1N1. Thus, there was hoarding of Tamiflu® during the 2009 swine flu pandemic.

So far, Relenza® is effective against both strains of influenza. There are health concerns about the drug, however, so it has not been marketed as widely. It is considered an important backup drug in case the H1N1 swine flu develops resistance to Tamiflu®, since there are only two drugs prescribed to treat swine flu.

An additional drug has been developed that has been used on an emergency basis in the United States. This is the compound peramivir. It has not been approved by the Food and Drug Administration (FDA), however. Peramivir is an alternate treatment for H1N1 swine flu, for people that cannot take the other drugs.