Scientists see Norwalk virus' Achilles heel

March 19, 2008

University Park, Pa. — Using the Canadian Light Source synchrotron,  an international team including Penn State researchers has determined the detailed structure of the enzyme the Norwalk virus uses to make copies of its genetic code in order to replicate itself. The information is crucial to developing drugs that could be used to treat outbreaks of Norwalk and other related viruses.

Outbreaks of Norwalk virus are notorious for the havoc they can cause to people living in close quarters, from cruise ships to hospital wards, often causing severe dehydration due to vomiting and diarrhea. The currently untreatable bug belongs to a superfamily of viruses that stores their genetic code as RNA, including polio, hepatitis C, foot-and-mouth disease and even the common cold.  The problem with all of these viruses is the lack of effective treatments.

The Norwalk virus uses the enzyme, RNA polymerase, to make new strands of RNA using an existing RNA strand as a template. The copying, which occurs within an area of the enzyme called an active site, can be blocked—or inhibited--with a drug molecule shaped to fit the site, like a key in a key hole.

“These are the first structures showing the enzyme doing its job interacting with RNA,” says lead author University of Calgary researcher Ken Ng.  “These structures provide ideas of of how we could develop new antiviral drugs that block the enzyme’s activity.”

In addition to Dr. Ng, the team includes Blake Peterson, associate professor of chemistry at Penn State University and a faculty member at University of Kansas; former Penn State graduate student Daniel Harki, now at California Institute of Technology; and researchers from University of Oviedo (Spain),  the University of Kansas and the Canadian Light Source. Their work appears in the March 21 issue of the Journal of Biological Chemistry.

“The best doctors can do with Norwalk patients is treat the symptoms. We have the polio vaccine, but many other serious diseases, like hepatitis C, lack effective treatments,” explains Dr. Ng. “This polymerase is closely related in all of these viruses, so an inhibitor drug that works against Norwalk virus could also work in treating hepatitis C.”

This research was supported by the Alberta Heritage Foundation for Medical Research, Alberta Ingenuity Centre for Carbohydrate Science, Alberta Synchrotron Institute, Natural Sciences and Engineering Research Council, Canadian Institutes of Health Research and U.S. National Institutes of Health.

Reference: Dmitry F. Zamyatkin, Francisco Parra, Jose M. Martin Alonso, Daniel A. Harki, Blake R. Peterson, Pawel Grochulski and Kenneth K.-S. Ng. 2008. Structural insights into mechanisms of catalysis and inhibition in Norwalk Virus polymerase. Journal of Biological Chemistry, Vol. 283, Number 12, pp. 7705-7712.  DOI: 10.1074/jbc.M709563200.

Courtesy of University of Calgary and Canadian Light Source
 

Last Updated March 19, 2009