Influenza affects millions of people in all parts of the world. The fact that influenza virus can spread through air increases the chance of influenza outbreaks. There are 3 to 5 million severe cases of influenza resulting in 290,000 to 650,000 deaths every year. Not as common as outbreaks, but in the 20th century four influenza pandemics appeared: Spanish influenza (1918, 50 million deaths), Asian influenza (1957, 2 million deaths), Hong Kong influenza (1968, 1 million deaths) and swine influenza pandemic (2009, 150,000 to 500,000 deaths). World health organization (WHO) emphasizes that influenza is the only pathogen that has a reasonable chance of causing a new pandemic in the near future. It is unlikely that current influenza vaccines and therapeutics will be sufficient to prevent a coming pandemic.
Presented within this thesis is a novel approach to irreversibly inhibit influenza virus with non-toxic and highly effective nanomaterials. These nanomaterials are designed so to bear glycan end-groups that bind to the influenza virus with high-affinity. Their design is such that binding determines a chain of events that leads to the irreversible loss of viral infectivity (i.e. virucidal mechanism). There are two key elements in the design of these materials. The first is the correct glycan sequence, terminating with sialic acid, needed to bind with high affinity to the influenza virus attachment ligand that is hemagglutinin. The second is a certain hydrophobic content in the drug, needed to impart the irreversibility in the antiviral effect. We show that when both elements are present, a virucidal non-toxic drug can be achieved either with gold nanoparticles or with cyclodextrins.
With these materials several human influenza strains of type A and B were inhibited with virucidal mechanism. Furthermore, ex-vivo and in-vivo antiviral activity of the nanomaterials with cyclodextrin core was investigated against a very aggressive influenza A strain. Ex-vivo studies clearly demonstrated that the mechanism of inhibition is virucidal. In the in-vivo studies, nanomaterials prevented the mice to loose weight and body temperature; significantly reduced the virus concentration in the lungs and in the nose. These materials can be further developed to target animal strains of the influenza virus. This is particularly important since influenza pandemics usually appear when humans are infected with a new animal strain such as avian and swine influenza
