By EMIL VENERE
New research findings point toward a class of compounds that could be effective in combating infections caused by enterovirus D68, which has stricken children with serious respiratory infections and might be associated with polio-like symptoms in the United States and elsewhere.
The researchers have used a technique called X-ray crystallography to learn the precise structure of the original strain of EV-D68 on its own and when bound to an anti-viral compound called pleconaril. The ongoing research could lead to the development of drugs that inhibit infections caused by the most recent strains of the virus, said Michael G. Rossmann, Hanley Distinguished Professor of Biological Sciences at Purdue University.
A molecule called a pocket factor is located within a pocket of the virus’s protective shell, called the capsid. 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 to replicate itself.
The antiviral compound pleconaril also binds into the pocket, inhibiting infection.
“The compound and the normal pocket factor compete with each other for binding into the pocket,” Rossmann said. “They are both hydrophobic, and they both like to get away from water by going into the pocket. But which of these is going to win depends on the pocket itself, the pocket factor and properties of the antiviral compound.”
The findings are detailed in a paper appearing in the journal Science on Friday, Jan. 2. The paper was authored by Yue Liu, a graduate student; Ju Sheng, a technical assistant; Andrei Fokine, Geng Meng, Woong-Hee Shin, and Feng Long, post doctoral research associates; Richard Kuhn, professor and head of Purdue’s Department of Biological Sciences; Daisuke Kihara, a professor of biological sciences and computer science; and Rossmann.
“In this work we only focused on the very original EV-D68 isolate, which was discovered in 1962,” Liu said. “Strains in the current outbreaks have minor differences.”
Although pleconaril is not active against current strains of EV-D68 tested thus far, it is active against the original isolate. Small changes in the structure of pleconaril are likely to lead to anti EV-D68 inhibitors against a broader spectrum of isolates.
An upsurge of EV-D68 cases in the past few years has been seen in clusters of infections worldwide. In August 2014 an outbreak of mild-to-severe respiratory illnesses occurred among thousands of children in the United States of which 1,149 cases have been confirmed to be caused by EV-D68. The virus also has been associated with occasional neurological infections and “acute flaccid myelitis,” characterized by symptoms including muscle weakness and paralysis.
Purdue researchers became interested in studying pleconaril’s potential effectiveness against EV-D68 after an outbreak of about 20 cases of acute flaccid paralysis was reported in California between 2012 and 2014. Out of those cases, two tested positive for EV-D68.
“This suggests the potential association of EV-D68 with polio-like illness,” Liu said.
The researchers are working with the Centers for Disease Control and Prevention and are studying the newer strains to determine their structures.
The research was supported by the National Institutes of Health.