When the Ebola virus infects a host cell, the first thing it does is attach itself to the cell using a glycoprotein. A newly obtained structure of that glycoprotein—the highest resolution one to date—now reveals a vulnerability in the virus’s infection machinery. Given the lack of approved therapies to combat the virus, this work gives medicinal chemists a weak point to target as they try to design molecules that stop Ebola’s deadly spread.
Researchers led by Oxford University’s David Stuart solved the structure of the virus glycoprotein to a resolution of 2.2 Å in complex with two different molecules that scientists have shown can reduce infection in rodents: ibuprofen and the chemotherapy drug toremifene (Nature 2016, DOI: 10.1038/nature18615).
Stuart’s team found that both chemicals bind in a buried pocket of the virus glycoprotein. The binding of these chemicals likely pushes the glycoprotein prematurely into a state where it can’t infect host cells, Stuart says.
Drug designers “will be salivating about that binding pocket,” comments Kartik Chandran, who studies Ebola at Albert Einstein College of Medicine. But it’s premature to think that toremifene or ibuprofen will end up as an Ebola drug, he cautions.
“People get really excited about repurposing FDA-approved drugs for fighting Ebola because they’ve already been proven safe in humans. But many small molecules that show promise in mice fail in macaques,” primates that are a more realistic human proxy than rodents, Chandran says. “The dose makes the drug—and toremifene doesn’t bind strongly to the virus glycoprotein. You may not want to give people who are already very sick high doses of a chemotherapy drug.” Chemists, however, could optimize compounds to fit much tighter in the binding pocket, now that they have this structure to work from, Chandran says.
“There’s quite some additional space in the binding pocket, and ibuprofen and toremifene aren’t very similar structures,” Stuart says. There are a lot of changes you could imagine that would optimize binding, he says.
In fact, many medicinal chemists may be surprised that toremifene and ibuprofen destabilize the pathogen’s virus glycoprotein, comments Felix Wieland, who studies Ebola at the University of Heidelberg. Most small molecules act like a stabilizer to proteins. This unusual feature might be capitalized upon for drug design, he notes.