How designer drugs can target flu


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Fighting flu is no exact science. Each new flu season means another inoculation with a new vaccine and each one is only science’s best guess at what’s coming next and may not help at all in immune-compromised systems. Now new research from the University of Washington in Seattle suggests the answer may lie in a designer drug that fights off infection regardless of the state of an individual’s immune response.


A spike in numbers

Close up, the flu virus looks like a ball covered with around 500 spikes. Each of these individual “spikes” is actually one of two different proteins: hemagglutinin (HA) or neuraminidase (NA). It is the HA spike that attaches to cell when the virus invades the body and the various different combinations of HA and NA spikes that give flu viruses their names — for example, H1N1 or H3N2.

The structure of these the two protein spikes comprises an inner stem and an outer covering — the inner stem is similar for both proteins but the outer part can vary significantly.

The constant mutation of the HA and NA spikes is the reason why flu vaccines change from season to season — following patterns of development, every year, experts make their best prediction of what the new strain will look like.

It is when radically new and unpredictable mutations occur that dangerous pandemics take hold. Ideally, scientists hope to find a vaccine that will act against a variety of flu strains.


Designing molecules

It’s been previously shown that our natural antibodies can prevent flu by attacking the HA stem. But these antibodies work, in part, by activating our immune response. This means they depend on a healthy immune system — something not present in babies, the elderly or those with compromised immune systems.

A team including researchers Deborah Fuller and computational protein design expert David Baker, at the University of Washington in Seattle, wondered if, by designing molecules that can bind to the HA stem in the same way antibodies do, they could protect the body against a flu infection.

Because their new molecules didn't engage the immune system the same way antibodies do, and because it was uncertain how stable and effective they would be, it was not clear whether they would be able to fight flu infection in animals and humans. So the researchers generated thousands of different versions to see how effectively they attached themselves to HA proteins from seven different influenza strains.


Better protection

Following their computer models, they found the resulting new molecule — which they called HB36.6 — also protected cells against influenza virus infections in laboratory-based in vitro experiments. Finally, they carried out tests of the new drug on mice. The team found that a one-time treatment with the new drug given up to 48 hours before exposure to the virus, offered complete protection.

Mice treated in this way survived with little to no weight loss. In addition, it was found that the new drug — which was given intra-nasally — could protect mice after they had been exposed to flu virus. HB36.6 was still effective either when it was administered as a single dose within a day after exposure, or when it was given daily for four days starting 24 hours after exposure.


Subtle synergy

Importantly, the protection does not seem to depend on a robust immune response, which is great news for everyone with a compromised immune system, as well as those who are still skeptical about getting their flu shot.

When the researchers repeated their experiments in two different immune-deficient mouse strains, they found that HB36.6 protected those mice as well. Compared with Oseltamivir, the researchers found that a single dose of HB36.6 provided better protection than 10 doses (taken twice a day for 5 days) of Oseltamivir — the anti-influenza drug currently marketed as Tamiflu.

The researchers also found that a low dose of HB36.6 — one not otherwise enough to fight off the illness — given after infection, in conjunction with twice-daily doses of Oseltamivir, was enough to keep the mice free of flu. This, they say, suggests a “synergistic effect” when combining the two drugs.

Their results, the researchers say, show how their drug designs have “potent anti-viral efficacy” and could mean positive things for anti-viral drugs that not only protect against catching flu but could also be used in treating it after exposure. The research is published in the journal PLOS Pathogens.