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Fighting flu with designer drugs: a new compound given before or after exposure fends off different influenza strains

A study published in PLOS Pathogens reports that a new antiviral drug protects mice against a range of influenza virus strains. The compound seems to act superior to Oseltamivir (Tamiflu) and independent of the host immune response.

Influenza viruses under the microscope look a bit like balls covered with spikes. The spikes are actually two different proteins, hemagglutinin (HA) and neuraminidase (NA). Both proteins consist of an inner stem region (which doesn’t differ much between flu strains), and a highly variable outer blob. The individual variants fall into designated groups, and this is how flu strains are categorized (for example as H1N1, or H3N5).

Ongoing mutations that change the HA and NA blobs are the reason why flu vaccines differ from season to season; they are based on researchers’ best guesses of what next year’s prominent strains will look like. And dangerous pandemic strains often have radically new blobs against which existing immunity is limited.

In the search for drugs that act broadly against different influenza strains, researchers had previously shown that antibodies against the HA stem region can prevent influenza infection. Such antibodies are protective, at least in part, because they activate the host immune response which then destroys the whole HA/antibody complex. The approach, then, depends on a fully functional immune system – which is not present in infants, the elderly, or immune-compromised individuals.

Inspired by the earlier work, Deborah Fuller from the University of Washington in Seattle, USA, who is interested in developing influenza drugs and vaccines, teamed up with David Baker, also at the University of Washington, who is an expert in computational protein design. Together with colleagues, they set out to design small molecules that – like the protective antibodies – bind to the HA stem, and to test whether these small molecules can protect against influenza infection. Designed to mimic antibodies, the small molecules bind the virus in a similar manner. However, because they don’t engage the immune system the way antibodies do, and because of questions of stability and potency, it was not clear whether they would be able to prevent infection in animals, or eventually, in humans.

Image of anti-influenza protein HB36.6
Designed anti-influenza protein HB36.6 (magenta) bound to the hemagglutinin from the H1N1 2009 pandemic virus
Image Credit: Koday et al.