Highly potent compound blocks Ebola virus infection and improves survival in animal model
A multi-institutional research team has discovered a highly potent small molecule that blocks Ebola virus infection by preventing changes required for viral entry.
The work, published in Nature Communications, is a result of an extensive collaboration among the University of Minnesota, Baylor College of Medicine’s Center for Drug Discovery, Boston University and the Florida Scripps Institute.
“This compound, named MWAC-3634, works in the opposite way from previously studied Ebola entry inhibitors,” said Dr. Fang Li, professor and co-director of the Midwest Antiviral Drug Discovery (AViDD) Center based at the University of Minnesota.
Earlier compounds destabilized the Ebola entry protein. MWAC-3634 stabilizes it, essentially locking the protein so the virus cannot make the changes required to enter a cell. That represents a new strategy for blocking infection.”
From billions of molecules to a lead compound
Researchers used DNA-Encoded Chemistry Technology to screen approximately 4.73 billion molecules directly against the Ebola entry protein, uncovering a promising chemical starting point.
“DNA-encoded libraries let us search billions of molecules in a single discovery campaign,” said Dr. Srinivas Chamakuri, assistant director of the Center for Drug Discovery in the Department of Pathology at Baylor.
That scale allowed us to explore chemical space far beyond a conventional screen and uncover a promising starting point we might otherwise have missed.”
Medicinal chemistry then transformed the initial hit into MWAC-3634. The compound inhibited authentic Ebola virus infection at extremely low concentrations with no detectable toxicity to cells under the conditions tested.
“The initial hit was only a starting point,” said Dr. Peter Dosa, research associate professor of medicinal chemistry at the University of Minnesota. “The starting compound was a mixture of closely related forms. By identifying the most active form, we substantially increased its potency.”
How the compound locks the entry protein
High-resolution structural studies showed that MWAC-3634 fits into a pocket in the Ebola entry protein and holds it in a stable state. Normally, the protein must change shape for the virus to fuse with and enter a host cell. Locking it in place blocks infection at one of its earliest stages.
Researchers found MWAC-3634 is 100 times more potent than previously reported small-molecule Ebola entry inhibitors.
“The structure allowed us to see exactly where MWAC-3634 binds and how it stabilizes the Ebola entry protein,” said Li. “That molecular view helps explain the compound’s high potency and gives us a blueprint for designing improved versions.”
In a lethal mouse model, 85.7% of mice treated orally with MWAC-3634 survived, compared with 28.6% of controls; 100% of mice treated by injection survived. Treated mice also had less weight loss, fewer signs of illness and lower virus levels. MWAC-3634 showed 69% oral bioavailability relative to intravenous dosing.
“The protection we saw with oral treatment is particularly encouraging,” said Dr. Robert Davey, professor of virology, immunology and microbiology and interim director of the National Emerging Infectious Diseases Laboratories at Boston University.
This is still an early-stage compound, and additional development and testing will be needed before we know whether it could be useful in people.”
Fan Bu is the lead author of the study. Bu, Gang Ye, Kiran L. Sharma and Bruno La Rosa contributed equally to the work. Fang Li is the senior author. Li, Peter Dosa, Srinivas Chamakuri and Robert Davey are co-corresponding authors.
The study combined DNA-encoded library screening, medicinal chemistry, structural biology, authentic Ebola virus testing, drug exposure studies and animal studies across four institutions. It was supported by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, including the Midwest AViDD Center (U19AI171954), and by NIH grant R01AI195592. MWAC-3634 is experimental and has not been approved or shown to prevent or treat Ebola virus disease in humans.
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