The new work, reported online this week (Oct. 4, 2006) in the Journal of Virology, describes the discovery of a peptide -- a small protein molecule -- that effectively blocks the influenza virus from attaching to and entering the cells of its host, thwarting its ability to replicate and infect more cells.
The new finding is important because it could make available a class of new antiviral drugs to prevent and treat influenza at a time when fear of a global pandemic is heightened and available antiviral drugs are losing their potency.
"This gives us another tool," says Stacey Schultz-Cherry, a UW-Madison professor of medical microbiology and immunology and the senior author of the new report. "We're quickly losing our antivirals."
The new drug, which was tested on cells in culture and in mice, conferred complete protection against infection and was highly effective in treating animals in the early stages of infection. Untreated infected animals typically died within a week. All of the infected animals treated with small doses of the drug at the onset of symptoms survived.
"Pretreatment with (the peptide) provided 100 percent protection against numerous subtypes (of flu), including the highly pathogenic H5N1 viruses...," according to the Journal of Virology report.
The new drug, known as "entry blocker," is a fragment of a larger human protein whose role in biology is to help things pass through membranes such as those that encapsulate cells.
Although the peptide's precise mechanism for thwarting flu remains to be deciphered, it seems to work by blocking the virus' ability to latch onto a key cell surface molecule that the virus uses to get inside cells. To survive and reproduce, viruses must gain access to cells where they make new infectious particles to infect yet more cells in a cascade of infection.
The scientific team emphasized that while the new drug shows great promise, much work remains to determine optimal dosage, efficacy and safety before the drug can be tested in a human patient. One possibility is that the new agent could be used as part of an anti-influenza cocktail of drugs, much like those used to treat HIV infection. The team hopes to move the research into preclinical phase as quickly as possible.
Currently, there are a few effective antiviral medications on the market for influenza, but they are beginning to show signs that they are losing their effectiveness, and scientists and health professionals worry that the flu virus, and especially the H5N1 bird flu virus, will evolve to the point where existing drugs are no longer effective. Drugs now on the market work by either preventing virus replication within the cell or preventing the release of viruses from the cell.
The peptide found by the Wisconsin group seems to work in an entirely different way.
"It attacks a completely different part of the virus life cycle," explains Curtis R. Brandt, a co-author of the study and a UW-Madison professor of medical microbiology and immunology and of ophthalmology and visual sciences. "The virus can't even get into the cell. The peptide is blocking the very earliest step in infection."
Antiviral drugs are considered to be a critical line of defense in the event of an influenza epidemic or pandemic. Vaccines are the most important defense, but new vaccines must be customized in response to an outbreak of disease and it can take as long as a year to formulate and manufacture vaccine in quantity. Antiviral drugs, it is anticipated, would be used to buy time to produce a vaccine in the event of a flu pandemic.
And one intriguing possibility, the Wisconsin scientists add, is that the drug might be able to help stimulate an immune response to flu as the peptide failed to block all of the virus particles in their experiments. A few persistent virus particles, while not enough to make a patient sick, could give the immune system the viral template it needs to mount an effective response, just like a vaccine.
The flu-thwarting qualities of the peptide were observed after similar peptides were found by Brandt and his colleagues to stop herpes simplex virus infection.
The Wisconsin work was supported by grants from the UW-Madison School of Medicine and Public Health Education and Research Committee, the National Institutes of Health and the Defense Advanced Research Projects Agency.