H1N1. H5N1. H7N9. The influenza virus comes in many varieties and goes by many names. Its diversity is its greatest asset: the ability to change two proteins on its surface-H and N in shorthand-let escape the immune system and complicates the work of the drug and vaccinemakers. Now researchers report that they have used computers to help them target a region of the virus that rarely changes, and they designed a small protein that makes the virus unable to infect cells and cause disease, at least in the mouse.
"It is a new way to rationally develop antiviral drugs," said veterinary microbiologist Jürgen Richt at Kansas State University, Manhattan, who was not involved in the study. "It is a beautiful paper and I think they are doing good work, but as always there is more to do."
Today PLoS Pathogens , scientists say they have developed small molecules to target a particularly vulnerable region of the hemagglutinin, one of two proteins that project from the viral surface like a flower. They home on the stem of the flower, part of the protein which is retained between the different virus strains. Scientists have previously shown that antibodies to the rod stop a wide range of influenza viruses cause an infection, and some are being developed as treatments. But the drug may have an advantage because the mouse studies have shown that monoclonal antibodies need help of other branches of the immune system that are sometimes compromised in older people, the group most vulnerable to the virus influenza. small molecule drugs are also much easier and less expensive to manufacture than monoclonal antibodies.
The researchers started with a small protein called HB36.5, which is known to bind to the hemagglutinin of influenza. Using a combination of laboratory tests and computer algorithms, the team tested various mutations in HB36.5, looking for single amino acid changes that would increase how closely related protein to a diverse group of hemagglutinin. Finally, tests have converged on a new protein mutations, that researchers HB36.6 doubled.
The scientists HB36.6 to a group of mice before and after infection with a lethal dose of influenza virus. When administered prophylactically, all mice survived and lost less weight than control animals infected with the same virus. When administered after infection, the protein was less effective, but still significantly reduced death and weight loss. Other tests have shown that HB36.6 stops the virus without the help of the immune system.
Koday et al. Creative Commons
Deborah Fuller, a microbiologist at the University of Washington, Seattle, who led the study, noted that HB36.6 is still a very long way shelf pharmacy. "This is a proof of concept," Fuller said. "Everything works in mice, it seems. They are not always the best indicator of what is going to work in humans. "However, Fuller and his team hope to move to clinical trials soon.
Although HB36.6 does not prove its value in human studies, researchers say it opens the door to a new class of antiviral drugs computer generated. Apart from the independent operation of the immune system, the approach may make it harder for the virus to become resistant to drugs. As combination therapies used to treat HIV, scientists could design a sequence of slightly different proteins that target the region of the hemagglutinin stem, making it harder for the virus to evade the drug with a single mutation.
Richt accepts the results are encouraging, but underlines that HB36.6 can have limited use in the real world. Flu symptoms usually occur a few days after infection, and HB36.6 lost about half of its effectiveness when given 24 hours after infection in mice. "If we have a pandemic and everyone is nervous, and they want to take as a prophylactic, which could be ok," says Richt. But the ideal drug against flu would work against all strains when symptoms surface, which remains a major challenge.
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