Scientists Report Advance in Tackling Common Viral Respiratory Disease
Respiratory infections strike millions of people each year and collectively cause more deaths than any single infectious disease. For the first time, scientists have determined the structure of a key protein from a paramyxovirus, a leading cause of respiratory disease in children throughout the world. In the November issue of Nature Structural Biology, researchers describe the three-dimensional structure of a protein used by paramyxoviruses to latch onto, penetrate and exit the cells of the respiratory tract. Their study reveals clues for effective new drugs and highlights the benefits of structural biology in helping guide drug design against communicable diseases.
Paramyxoviruses cause several respiratory diseases in humans and animals. One of these viruses, parainfluenza, infects almost all children before they reach the age of 5, causing illnesses ranging from colds to pneumonia.
"This report is the most exciting discovery in the field in quite some time," says Fran Rubin, Ph.D., program officer for respiratory diseases at the National Institute of Allergy and Infectious Diseases (NIAID), which partially funded the study. "We have no vaccines or effective drugs to stop viruses like parainfluenza. This study opens new possibilities for drug development."
The study focuses on a protein called hemagglutinin-neuraminidase (HN), which is found on the surface of many paramyxoviruses. The protein plays a key role in infection, helping the virus recognize and enter cells and to spread to neighboring cells as the virus reproduces. Each of these properties depends on the unique shape of the protein and the chemical charges distributed across its surface.
Scientists have studied the design of similar proteins to develop effective drugs against other viruses, but the three-dimensional structure of paramyxovirus HN has remained unknown because researchers have been unable to "grow" these proteins into the crystals required for study. This has thwarted efforts to design new drugs that specifically attack the molecule.
The researchers in this study, led by Allen Portner, Ph.D., of St. Jude Children's Research Hospital in Memphis, Tenn., and Garry Taylor, Ph.D., of St. Andrews University in Scotland, used X-rays to probe the molecular structure of HN from Newcastle disease virus, a paramyxovirus that causes respiratory illness in chickens. "My laboratory has tried for years to find an HN protein that would permit us to take a look at its molecular structure, but many would not form the crystals required to get an X-ray picture," explains Dr. Portner. "Newcastle disease virus finally provided a protein that solved our problems." The scientists knew from genetic and biochemical analysis that this HN gene is very similar to the HN of other paramyxoviruses, making their results applicable to parainfluenza and related viruses.
Once they determined the HN structure, the researchers were surprised to learn that two different virus properties -- attachment and release from the cells lining the respiratory tract -- are controlled by the same region of HN. Because viruses must latch onto the cell before entering, this one region is critical for several virus functions. "What this means is we might be able to attack multiple facets of the virus through a single site," explains Dr. Taylor. "If we can design a molecule that blocks this site, we might have a drug that prevents all three key steps in virus infection -- attachment, cell entry and release."
As Dr. Portner states, "This study offers hope that we will one day be able to treat the infection before the damage is done, improving the health of many children and beating back a leading respiratory infectious disease."
Reference: S Crennell, et al. Crystal structure of the multifunctional paramyxovirus hemagglutinin-neuraminidase. Nature Struct Biol 7:1068-74 (2000).
NIAID is a component of the National Institutes of Health(NIH). NIAID supports basic and applied research to prevent, diagnose and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, tuberculosis, malaria, autoimmune disorders, asthma and allergies.
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