Enterovirus laid bare: X-ray structures

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  • Published: Jan 8, 2015
  • Author: David Bradley
  • Channels: X-ray Spectrometry
thumbnail image: Enterovirus laid bare: X-ray structures

EV-D68

False colou structure shows surface of enterovirus D68. Red regions are the highest peaks, and the lowest portions are blue. (Purdue University image/Yue Liu and Michael G. Rossmann)

X-ray crystallography has been by a team in the USA to obtain the precise structure of the original strain of enterovirus EV-D68 known to cause respiratory illness and polio-like symptoms in children as well as a second structure in which the virus is bound to the drug pleconaril. This ongoing research could lead to the development of drugs for inhibiting infection caused by the most recent strains of this virus, explains Michael Rossmann of Purdue University.

Details were published on 2nd January 2015 in Science authored by Rossmann and colleagues graduate student Yue Liu, technical assistant Ju Sheng, post-docs Andrei Fokine, Geng Meng, Woong-Hee Shin and Feng Long, Purdue biologists Richard Kuhn and Daisuke Kihara.

Acute flaccid myelitis

EV-D68 was first identified in California in 1962 and was thought of as a rather rare infection, however, cases have been on the increase in recent years, with incidences of clusters worldwide and a major respiratory outbreak in August 2014 among thousands of children in the USA. The virus can also cause neurological problems, namely "acute flaccid myelitis," which resembles polio in causing muscle weakness and paralysis. There is currently no vaccine nor effective antiviral agent.

Over the years, Rossmann, and collaborators in the pharmaceutical industry, have developed antiviral drugs for several other enteroviruses, which include the rhinoviruses that cause the common cold. Among those drugs is pleconaril, first identified in the 1990s but unapproved because of a contraindication with chemical contraception.

Human hosts out of pocket

The virus infects human host cells by utilising a molecule, a so-called "pocket factor" that is held within a pocket in the protective shell of the virus, the capsid, and is squeezed out when the virus binds to a human cell, this process destabilises the viral shell and allows its genetic material to enter the cell and replicate. Pleconaril also binds to this pocket and so halts infection.

"The compound and the normal pocket factor compete with each other for binding into the pocket," Rossmann explains. "In this work we only focused on the very original EV-D68 isolate, which was discovered in 1962," team member Liu explains. "Strains in the current outbreaks have minor differences." As such, pleconaril is inactive against current strains, but analogues may act against EV-D68. The researchers are therefore working with Steve Oberste's group at the US Centers for Disease Control and Prevention to determine the structures of the recent active strains so that analogues might be found. "Designing the best possible compound for these newer strains will take more time, but I hope that in a year or so we might have something," Rossmann adds.

"The next steps will be looking at more recent isolates and comparing these with the earlier isolate we have worked on so far, both in terms of the structure and its infectivity when complexed with Pleconaril. In the 1990s we worked successfully with the ViroPharma company to design Pleconaril which was tested clinically in Phase 1, 2 and 3 trials. We will need to find a similar partner to make our results clinically relevant," Rossmann told spectroscopyNOW.

Related Links

Science, 2015, 347, 71-74: "Structure and inhibition of EV-D68, a virus that causes respiratory illness in children"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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