May 13, 2008

• Discovered RHDV virus binding mechanism

• New target for drug design

• International research effort

BIRMINGHAM, Ala. - UAB (University of Alabama at Birmingham) scientists were part of an international research team that discovered the unique way certain viruses invade healthy cells, opening the door to new therapies that could block those viruses.

Viruses need a point-of-entry to a cell, typically binding to an antigen on the cell surface as a means of gaining access. The team, reporting in the March issue of the Journal of the American Chemical Society, used a special nuclear magnetic resonance (NMR) technique to precisely identify the point-of-entry on a healthy cell used by rabbit hemorrhagic disease virus (RHDV), a member of the calicivirus family.

The NMR studies definitively identified the main target of the RHDV virus as L-fucose, a sugar found on antigens on the surface of the target cell.

"We now know the chemical signature of the sugar that RHDV zeroes-in on as it invades a cell," said N. Rama Krishna, Ph.D., professor of biochemistry and molecular genetics and a study co-author. "We can counterattack by designing a drug with the same signature but made even more attractive to the virus, so that the virus binds to the drug instead of binding to the target cell.

Krishna says the real significance is that this NMR technique can be used to design anti-viral drugs for similar viruses including other caliciviruses, a family that includes Norwalk and Hepatitis E viruses that cause disease in humans. In fact, an editorial on the study appearing in the April 17th issue of the journal Nature highlighted this work for its impact on the potential development of novel anti-viral drugs.

"This application can be widely used to search for and identify the likely contact points on cell surface antigens that different viruses use as their point-of-entry to the cell," Krishna said. "By inducing the virus to preferentially bind with a drug that mimics the contact point, we think we can prevent it from infecting a cell."

Krishna's laboratory at UAB, one of the most sophisticated in the world in the quantitative use of the special technique called saturation-transfer difference NMR (STD-NMR), collaborated with Thomas Peters and Christoph Rademacher of the University of Luebeck, Monica Palcic of the Carlsberg Laboratory, and Francisco Parra of Instituto Universitario de Biotecnologia de Asturias in identifying the sugar recognized by the RHDV virus.

They placed antigens from the cell bodies in a solution with virus-like particles (VLPs), essentially an inactive virus. The hydrogen signals from the virus were irradiated with radiofrequency pulses. The energy received by the VLPs, called saturation, is passed on to the cell antigens at the binding site.  he amount of saturation in those antigens can be measured, thus identifying which particular sugar on the antigens gets "hot". Those sugars on the antigens, in this case the L-fucose, are the virus target.

"This is a compelling argument for the routine use of the STD-NMR technique in drug design and development in general - it is not limited to anti-virals. Interestingly, the method was originally developed in Germany for screening compound libraries, and is now a popular technique in the pharmaceutical industry for identifying lead compounds" Krishna said.

NOTE: The University of Alabama at Birmingham is a separate, independent institution from the University of Alabama, which is located in Tuscaloosa. Please use University of Alabama at Birmingham on first reference and UAB on second reference.