Mar. 29, 1999 The broad family of viruses whose members cause measles, mumps and serious respiratory infections in infants may be distantly related to the family that includes HIV, influenza and Ebola viruses, researchers at Northwestern University and the Howard Hughes Medical Institute at Northwestern have shown.
The finding, reported in the March 26 issue of the journal Molecular Cell, comes from precise determination of the three-dimensional structure of a key protein molecule, whose form suggests that all these viruses enter cells by a remarkably similar mechanism.
"The structure of this molecule shows that a widely dissimilar virus, a virus that everybody thought was very different from the other group, ends up in fact having remarkable similarities," says virologist Robert A. Lamb, an investigator in the Howard Hughes Medical Institute at Northwestern and one of two senior authors on the study. "It suggests a common ancestor among all these viruses, where one would have thought them not to be related at all."
A team led by Lamb, who is John Evans Professor of Biochemistry, Molecular Biology and Cell Biology at Northwestern, and X-ray crystallographer Theodore S. Jardetzky, assistant professor in the same department, determined the precise molecular shape of a fragment of the "fusion protein" of a paramyxovirus using the extremely brilliant X-rays produced by the Advanced Photon Source synchrotron at Argonne National Laboratory in Illinois.
The fusion protein is embedded in the membrane that envelops the virus. It serves as a grappling hook that snags the membrane of a host cell and pulls the two membranes together so that they fuse into one, like soap bubbles, dumping the viral genes into the host cell where they take over the cellular machinery to make more viruses.
Improved understanding of the fusion mechanism among these various viruses may lead to completely new approaches to blocking infection by preventing viruses from entering host cells, Jardetzky said.
"The fusion protein was of particular interest, because for HIV it's been shown that if you can inhibit the fusion protein, you can block viral entry," Jardetzky said. "The mechanism by which the virus causes the two membranes to fuse is turning out to be a good target for inhibitors. There are some peptides in clinical trials that will block HIV entry specifically by attaching to this protein."
Lamb said that the goal would be to design small molecules that would make better drug candidates than peptides, which are large protein-like molecules that are difficult to deliver continuously throughout the body. "The very related structural features of these fusion proteins may help in developing common strategies for therapeutic approaches, especially for viruses for which vaccines have not proven effective," he said.
In addition to measles, mumps, croup and viral pneumonia, the paramyxovirus family also includes respiratory syncytial virus, the leading cause of hospitalization of children under 2. The current treatment for RSV, using a mist of a powerful viral replication inhibitor, causes side effects and can even pose risks to caregivers.
Other paramyxoviruses cause devastating diseases of wildlife and livestock, such as canine distemper -- normally a virus of dogs, but which also ravaged the lion population of the Serengeti Plain -- and Newcastle disease of chickens.
Other authors on the Molecular Cell paper are graduate student Kent A. Baker and postdoctoral researcher Rebecca E. Dutch. The research was funded by the National Institutes of Health, the Howard Hughes Medical Institute and the Pew Scholars Program in Biomedical Sciences.
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