A breakthrough in the fight against mosquito-borne viruses could one day help protect patients from devastating neurological complications. A researcher at The University of Alabama in Huntsville (UAH) is working to move that possibility closer to reality. Dr. Victor Ogungbe, an associate professor of chemistry and UAH alumnus, is leading a five-year, $3.67 million research project funded by the National Institutes of Health (NIH) that is focused on advancing potential treatments for alphaviruses, a group of mosquito-borne viruses for which there are currently no vaccines or therapeutics currently approved for human use. UAH is a part of The University of Alabama System.
The R01 research project will investigate small-molecule compounds designed to block viral replication and evaluate their potential to protect the blood-brain barrier, a critical defense that helps shield the brain from harmful substances and pathogens. The research addresses a significant public health challenge. As outbreaks emerge or spread, the development of effective antiviral treatments could help strengthen preparedness and reduce the potential for serious illness and broader societal impacts.
"The project offers an opportunity to advance our work towards clinical development of a safe treatment option for a highly pathogenic virus," Ogungbe says.
The initiative focuses on inhibitors targeting the protease domain of nonstructural protein 2 (nsP2), a viral protein that plays an important role in alphavirus replication. The nsP2 protease is a part of a virus that acts almost like molecular scissors, cutting proteins into the pieces the virus needs to reproduce and spread. By blocking this protein's activity, the research team aims to identify and refine compounds that can stop the virus from multiplying in this way.
Previous findings have demonstrated that the compounds under investigation can inhibit alphavirus replication in cell cultures and protect mice against alphavirus infection, providing a foundation for further development.
"We have a well-established proof-of-concept," Ogungbe explains. "Our approach differs in that we are laser-focused on advancing very selective nsP2 protease inhibitors toward development, and we have a chemical space that is synthetically accessible, modular and scalable."
The researcher's team will pursue two primary objectives: improving the potency of lead compounds through structure-activity relationship studies, informed by efficacy testing in animal models, and evaluating whether the compounds can help preserve blood-brain barrier integrity during alphavirus infection. The research will include collaboration with Professor Aarthi Narayanan of George Mason University.
Protecting the brain's natural defenses
The blood-brain barrier regulates the movement of substances between the bloodstream and the brain. During severe viral infections, inflammation can compromise the barrier, increasing its permeability and potentially contributing to brain swelling and other neurological injuries. Understanding whether early antiviral intervention can limit this damage could help researchers identify strategies to reduce the neurological consequences of alphavirus infections.
To investigate this process, the research team will use organ-on-a-chip models of the blood-brain barrier. These laboratory systems can replicate key features of human biological tissues, allowing researchers to study barrier function and disease processes under controlled conditions. The models will enable repeated sampling on both sides of the barrier to assess permeability and viral particle levels. Researchers will use these capabilities to evaluate multiple inhibitors at different doses over extended periods.
"Organ-on-a-chip models provide a way to study the blood-brain barrier in ways that are very challenging in animal models," Ogungbe notes. "We can do repeated sampling on both sides of the barrier to check permeability and viral particle levels, which is currently very costly and technically limiting in animal models. This is especially true when evaluating multiple inhibitors at different doses."
A long-term investment in scientific discovery
R01 awards provide sustained support for researchers to investigate important scientific questions, test new approaches and generate evidence that can advance medicine and public health.
The work also has implications for biodefense preparedness. By investigating compounds that could be developed into effective countermeasures, researchers aim to expand the options available to respond to dangerous viral threats and improve readiness for future outbreaks.
"We hope to expand the biodefense countermeasures toolbox for pathogenic select agents and develop medical interventions that can be scaled up quickly if and when needed," Ogungbe says.
As the project progresses, the team will work to refine promising compounds, evaluate their protective effects and deepen scientific understanding of nsP2 and its role in alphavirus pathogenicity. These efforts help lay the foundation for new medical interventions against viruses for which treatment options remain limited.
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