A University of Minnesota-led multi-institutional research team has discovered a highly potent small molecule that blocks Ebola virus entry by stabilizing the virus’s entry protein and provides strong protection when given orally in a preclinical model.

The study, recently published in Nature Communications, resulted from extensive collaboration among the University of Minnesota, Baylor College of Medicine, Boston University and the University of Florida Scripps Institute, with support from the NIH-funded Midwest Antiviral Drug Discovery (AViDD) Center, based at the University of Minnesota.

MWAC-3634 targets the Ebola virus entry protein. All previously structurally characterized small molecules targeting this protein destabilized it. MWAC-3634 instead stabilizes the entry protein, preventing the shape changes required for viral entry. It is also at least 100 times more potent than previously reported small-molecule Ebola entry inhibitors.

“This compound works oppositely from prior Ebola entry inhibitors. Earlier compounds destabilized the entry protein. MWAC-3634 stabilizes it, essentially locking it so the virus cannot make needed changes to enter a cell.”

Fang Li, PhD, University of Minnesota Medical School

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.”

Srinivas Chamakuri, PhD, Baylor College of Medicine

Stereochemical analysis of the initial hit identified MWAC-3634 as the most active form. Against authentic Ebola virus, the compound inhibited infection with an IC50 of 0.65 nM and showed no detectable toxicity to cells under the conditions tested.

“The initial hit was only a starting point. The starting compound was a mixture of closely related forms. By identifying the most active form, we substantially increased its potency.”

Peter Dosa, PhD, University of Minnesota

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.

“The structure allowed us to see exactly where MWAC-3634 binds and how it stabilizes the Ebola entry protein. That molecular view helps explain the compound’s high potency and gives us a blueprint for designing improved versions.”

Fang Li, PhD

In a preclinical model, oral treatment with MWAC-3634 substantially improved survival, reduced signs of illness and lowered virus levels. The compound also showed 69% oral bioavailability relative to intravenous dosing.

“The protection we saw with oral treatment is particularly encouraging. 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.”

Robert Davey, PhD, Boston University

Fan Bu is the lead author of the study; Bu, Gang Ye, Kiran L. Sharma and Bruno La Rosa contributed equally to the work. Li is the senior author; Li, Peter Dosa, Srinivas Chamakuri and Robert Davey are co-corresponding authors.

The study combined DNA-encoded library screening, stereochemical analysis, 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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Journal: Nature Communications
DOI: 10.1038/s41467-026-77332-3
Funding: National Institute of Allergy and Infectious Diseases; NIH grant R01AI195592; Midwest AViDD Center (U19AI171954)