TSRI scientists pinpoint Ebola’s weak spots

Determining proper balance in targeting two Ebola proteins could be key to building improved therapeutics

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LA JOLLA, Calif.—Scientists at The Scripps Research Institute (TSRI) say they now have a high-resolution view of exactly how the experimental therapy ZMapp targets Ebola virus. The new study is also reportedly the first to show how an antibody in the ZMapp “drug cocktail” targets a second Ebola virus protein, called sGP, whose vulnerable spots had previously been unknown. The study was published Aug. 8, 2016 in the journal Nature Microbiology.
“This sGP protein is tremendously important,” said Erica Ollmann Saphire, a TSRI professor who co-led the study with Andrew Ward, a TSRI associate professor. “This is the roadmap we need to target the right molecules in infection.”
“Determining the proper balance in targeting these two Ebola proteins will be key to building improved therapeutics,” added Ward.
Scientists need detailed images of Ebola virus’s molecular structure, TSRI notes and , like military reconnaissance, structures can show where Ebola is vulnerable and how medical treatments can neutralize the enemy. TSRI scientists are harnessing an imaging technique called cryo-electron microscopy to create high-resolution, 3-D images of Ebola virus and the antibodies that fight it.
“We’re at the cutting edge of our ability to resolve high-resolution protein complexes,” said C. Daniel Murin, a TSRI research associate and co-first author of the new study with fellow TSRI research associate Jesper Pallesen.
In the new study, the researchers used cryo-electron microscopy to see exactly how Ebola virus interacts with the three antibodies in the ZMapp experimental therapy produced by Mapp Biopharmaceutical, also a study collaborator.
The researchers had imaged these interactions at a low resolution in a 2014 study, but the new study revealed substantially more details, including the exact angles the antibodies use to approach the molecule on the surface of the virus, termed its surface glycoprotein (GP), and the individual amino acid contact points at which the antibodies bind GP. This information provides new clues to researchers trying to make the antibodies even more effective.
“The three components of ZMapp, now resolved at high-resolution, can be further engineered in a structure-based manner for improved potency,” said Ward.
Next, the researchers took a closer look at one of the three antibodies that make up ZMapp, called 13C6. This antibody is unique because it can also target the soluble Ebola protein sGP.
sGP’s role in infection is a mystery. Ebola virus makes the protein profusely, indicating that it is important, but then sGP appears just to float in a person’s blood serum. One theory is that sGP may be essential in the natural host “reservoir.”
“Eighty to ninety percent of what Ebola virus makes in infection is this shed molecule,” said Saphire. “It’s like a smoke screen, and we need to know where it is similar to our target GP and where it is different.”
To add to the mystery, Ebola makes GP and sGP using the same gene. A small difference in the way the gene is read changes how the molecules are shaped and changes their roles.
One obstacle to understanding sGP is that it is too small to be seen with cryo-electron microscopes. To solve this problem, the researchers added “bulk” by pairing sGP with antibodies, including 13C6. This allowed them to kill two birds with one stone—they could see sGP’s structure while also studying how antibodies interact with it.
The new image shows the binding sites, or “epitopes,” that the antibody targets. “We can see hot spots on this virus that we can hit,” said Pallesen.
This study is the latest research from the Viral Hemorrhagic Fever Consortium, an international partnership of research institutes led by Saphire. The researchers said collaboration with the consortium was key to this study, allowing scientists to share samples and data, including viral genetic sequences isolated from patients in the most recent Ebola outbreak.
SOURCE: TSRI news release

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