"We found that when nanoparticle dendrimers containing sialic acid are administered intra-nasally to mice that had been exposed to a lethal dose of influenza A virus, 75% of the mice survive," explains team leader Robert Linhardt of Rensselaer Polytechnic Institute in New York.

The nanoparticles contain clusters of sialic acid residues bound to the hemagglutinin trimer located on the surface of the virus, he tells our sister site nanotechweb.org. The acid residues bind so tightly to the virus that they prevent it from infecting lung tissue. What is more, the residues are placed together extremely closely (just 3 nm apart) so that they cannot be cleaved by the neuraminidase enzymes present in the influenza virus. This means that these agents cannot be inactivated.

Targeting hemagglutinin

Neuraminidase inhibitors, such as oseltamivir and zanamivir, are currently used to treat influenza. However, these are becoming less effective as drug resistance builds up. "Our nanoparticle dendrimers target hemagglutinin and thus work on strains of influenza that are resistant to neuraminidase inhibitors," says Linhardt.

"Since binding of the virus to sialic acid residues in human lung tissue is an essential step in infection, we believe that it will be difficult for the influenza virus to develop resistance to these agents. Our nanoparticle dendrimers could be used either together with neuraminidase inhibitors or on their own to more effectively treat both standard and resistant influenza strains."

Inter-ligand spacing is key

Jennifer Wang of the University of Massachusetts Medical School, who was not involved in this work, says that when variations of dendrimers are compared in influenza assays, inter-ligand spacing is found to be a "key determinant" for antiviral activity. "Defining the physical properties by which dendrimers optimally bind to the influenza virus is thus a major advance for when it comes to designing effective decoys to combat influenza."

The experiments described in this work have only been performed on mice so far, so they need to be extended and validated in other animal models before they can be considered for human trials, adds Linhardt. "We also need to do a considerable amount of additional basic research on the nanoparticle dendrimers to better understand the mechanisms by which they work and how safe they are."

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