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Zika Virus Structure Revealed

Purdue scientists make critical advance in development of treatments

A team led by Purdue University researchers is the first to determine the structure of the Zika virus. The findings provide insights critical to the development of effective antiviral treatments and vaccines, according to the investigators. Their report was published in Science.

The team also identified regions within the Zika virus structure where it differs from other flaviviruses, the family of viruses to which Zika belongs. Flaviviruses include dengue, West Nile, yellow fever, Japanese encephalitis, and tick-borne encephalitic viruses.

“The structure of the virus provides a map that shows potential regions of the virus that could be targeted by a therapeutic treatment, used to create an effective vaccine or to improve our ability to diagnose and distinguish Zika infection from that of other related viruses,” said Dr. Richard Kuhn, director of the Purdue Institute for Inflammation, Immunology and Infectious Diseases, who led the research team. “Determining the structure greatly advances our understanding of Zika, a virus about which little is known. It illuminates the most promising areas for further testing and research to combat infection.”

Zika virus transmission has been reported in 33 countries. Of the countries where Zika virus is circulating, 12 have reported an increased incidence of Guillain-Barré syndrome, and Brazil and French Polynesia have reported an increase in microcephaly, according to the World Health Organization (WHO). In February, the WHO declared the Zika virus to be “a public health emergency of international concern.”

“We were able to determine through cryo-electron microscopy the virus structure at a resolution that previously would only have been possible through x-ray crystallography,” said Dr. Michael Rossmann, a professor of biological sciences at Purdue. “Since the 1950s, x-ray crystallography has been the standard method for determining the structure of viruses, but it requires a relatively large amount of virus, which isn't always available; it can be very difficult to do, especially for viruses like Zika that have a lipid membrane and don’t organize accurately in a crystal; and it takes a long time. Now we can do it through electron microscopy and view the virus in a more native state. This was unthinkable only a few years ago.”

The researchers studied a strain of Zika virus isolated from a patient infected during the French Polynesia epidemic. The team found that the virus’ structure was similar to that of other flaviviruses, with an RNA genome surrounded by a lipid membrane inside an icosahedral protein shell. The strong similarity with other flaviviruses was not surprising and is perhaps reassuring in terms of vaccine development already under way, according to the researchers.

The team found that all of the known flavivirus structures differ in the amino acids that surround a glycosylation site in the virus shell. The shell is composed of 180 copies of two different proteins. These, like all proteins, are long chains of amino acids folded into particular structures to create a protein molecule, Rossmann said.

The glycosylation site where the Zika virus differs from other flaviviruses protrudes from the surface of the virus. A carbohydrate molecule consisting of various sugars is attached to the viral protein surface at this site. As the virus projects a glycosylation site outward, an attachment receptor molecule on the surface of a human cell recognizes the sugars and binds to them, Kuhn said. The virus is like a menacing stranger luring an unsuspecting victim with the offer of sweet candy. The human cell gladly reaches out for the treat and is caught by the virus, which, once attached, may initiate infection of that cell.

The glycosylation site and surrounding residues on the Zika virus may also be involved in attachment to human cells, and the differences in the amino acids between different flaviviruses could signify differences in the kinds of molecules to which the virus can attach and the different human cells it can infect, Rossmann said.

“If this site functions as it does in dengue and is involved in attachment to human cells, it could be a good spot to target an antiviral compound,” he remarked. “If this is the case, perhaps an inhibitor could be designed to block this function and keep the virus from attaching to and infecting human cells.”

The team plans to conduct further testing to evaluate the different regions as targets for treatment and to develop potential therapeutic molecules, Kuhn said.

Source: Purdue University; March 31, 2016.

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