Researchers have discovered new details about the structure of a virus that causes potentially fatal brain swelling and paralysis in children, pointing toward designs for antiviral drugs to treat the disease.

The virus, enterovirus 71 (EV71), causes hand, foot, and mouth disease, and is common throughout the world. Although that disease typically is not fatal, the virus has been reported to cause encephalitis, a potentially fatal illness found primarily in the Asia-Pacific region.
 

A research team from Purdue University has proposed a way to design antiviral drugs to treat the infection. Findings from that team are detailed in a paper in Science. Another team, led by researchers at Oxford University, reported its findings in a paper in Nature Structural & Molecular Biology.

“Taken together, the findings in both papers are useful when you are trying to stop the virus from infecting host cells,” says Michael G. Rossmann, Purdue’s Hanley Distinguished Professor of Biological Sciences. “The common theme is that they both report for the first time on the structure of this virus, and this tells us how to design compounds to fight the infection.”

Both teams used X-ray crystallography to determine the virus’s structure, showing similarities to features on related enteroviruses, including poliovirus. However, a key feature is different in that a small molecule called a “pocket factor,” located within a pocket of the protective shell of the virus, is partially exposed in EV71.

When the virus binds to a human cell, the pocket factor is squeezed out of its pocket resulting in the destabilization of the virus particle, which then disintegrates and releases its genetic material to infect the cell and replicate.

Researchers led by Rossmann have developed antiviral drugs for other enteroviruses such as rhinoviruses that cause the common cold. The drugs work by replacing the pocket factor with a molecule that binds more tightly than the real pocket factor.

This hinders infection in two ways: The drug molecule fills the pocket, making it difficult for a virus to bind to a human cell. Also, because the drug binds tightly to the pocket, it stabilizes the virus and keeps it from disintegrating and releasing its genetic material into the host cell.

In EV71, a portion of the pocket factor sticks out of the pocket, exposing a hydrophilic tip, whereas the pocket factors in other related viruses are entirely enclosed in the pocket. In order to hinder EV71 infection, antiviral drugs must have a hydrophilic tip at one end to mimic the pocket factor.

Future work will include research aimed at developing an antiviral drug for EV71.

Release Date: March 1, 2012
Source: Purdue University