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Researchers Look for Ways to Deliver a One-Two Punch to Flu Viruses

Most antiviral drugs target only half of the cell-infection cycle of viruses such as H1N1. A team of researchers is looking to shut down the whole process



CDC

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The spread of a new strain of influenza A H1N1 virus across 50 countries worldwide since last month has helped remind the medical community that it needs to adapt to a virus that continuously reinvents itself.

Researchers at Rensselaer Polytechnical Institute (R.P.I.) in Troy, N.Y., say they are developing chemical compounds that could be used to create an antiviral weapon that would not only disrupt the work of the neuraminidase proteins (the "N" in H1N1), which allow the virus to escape an infected cell and infect healthy new cells, but also the hemagglutinin proteins (the "H" in H1N1), which bind to sialic acid on the healthy cell's surface, helping the virus penetrate the cell.

Although their work is in the very early stages and would likely take a decade before delivering a drug to treat flu victims, the researchers say they have developed six new compounds that have shown the ability to inhibit neuraminidase while blocking the hemagglutinin protein, so the latter cannot bind to the sialic acid present on the surface of a healthy cell and thereby gain entry. The compounds were made possible through the use of "click chemistry," which allows scientists to produce large amounts of new compounds quickly, says Robert Linhardt, the R.P.I. professor of biology, chemistry and chemical engineering who is leading the research effort. Click chemistry is an approach to synthesizing druglike molecules where a researcher uses a few practical and reliable well-documentedreactions to accelerate the drug discovery process.

Linhardt, whose report on his research appears in the June edition of European Journal of Organic Chemistry, is now looking to create a larger sample of new compounds, test their ability to neutralize both neuraminidase and hemagglutinin, and then work on making these compounds more potent. This would be followed by testing the compounds on animals and creating a medication that could be used in human trials, which then would require approval from the U.S. Food and Drug Administration (FDA)—a process that could take at least a decade.

Some are skeptical that Linhardt's team will succeed where others have failed. The development of something that "would soak up the virus in terms of providing a sialic acid receptor, a decoy so to speak—that would be useful," says Peter Palese, a microbiology professor at Mount Sinai School of Medicine in New York City. In such a scenario, the virus's hemagglutinin would try to bind to the antiviral compound (the decoy) rather than the cell itself. Unfortunately, he adds, researchers have been trying to do this for 60 years with little success. The problem, he says, has been creating a molecule that binds well enough to the hemagglutinin protein to truly block it.

Indeed, one of the challenges to developing a drug that targets both neuraminidase and hemagglutinin is the difference in their structure—hemagglutinin is shaped like a spike whereas neuraminidase has more of a mushroom shape—making it unlikely that the same chemical compound would effectively bind to each. In addition, "hemagglutinin is sort of flexible, so the attempts to block the binding of the virus have not been successful," says Alexander Klimov, chief of the Virus Surveillance and Diagnosis Branch of the U.S. Centers for Disease Control's (CDC) National Influenza Division.

Further complicating the ability to find one compound that works against both is the fact that each of these proteins has many of subtypes, so tuning an antiviral to block hemagglutinin might work against only a few different strains, adds Larisa Gubareva, a senior service fellow in the Virus Surveillance and Diagnosis Branch.

Still, Linhardt is committed to the multiple target approach. Most antiviral flu treatments, including GlaxoSmithKline's Relenza (zanamivir) and Roche Pharmaceuticals, Inc.'s Tamiflu (oseltamivir phosphate) target neuraminidase exclusively. They have been successful in reducing the duration and severity of illness for some swine flu victims (and the amount of time they put others at risk). But Linhardt believes a two-pronged approach would provide a safety valve for rapidly mutating viruses.

"When you target two steps you get synergism," he says. "The sum of the whole is greater than the sum of the parts. If you have a drug that's average against two receptors, it will be extraordinary against the target." His team's work has been helped by the National Institutes of Health's commitment to provide a five-year, $1-million grant.

"This is right now mostly a chemistry project," Linhardt says. "It's an incremental move in developing a new type of drug. There are a number of steps and several years before this could be available."

Much of the other work being done in respond to the H1N1 pandemic is to develop a vaccine that can be used to immunize people against this strain. Sanofi pasteur, the vaccines division of Bridgewater, N.J.–based sanofi-aventis, on May 27 received the new influenza A (H1N1) seed virus from the CDC, enabling that company to begin the production process for a vaccine. Biotech firm Novavax, Inc., in Rockville, Md., has begun developing a prototype swine flu vaccine using information the CDC posted to the Global Initiative on Sharing Avian Influenza Data (GISAID) database, launched in 2006 by a number of government organizations, science institutes and universities worldwide (including the World Health Organization, CDC, and the Max Planck Institute for Informatics) to encourage data-sharing in response to the global spread of the H5N1 avian flu.

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