AI-Powered Discovery Identifies Novel Monkeypox Virus Drug Target OPG153
Key Insights
Researchers used AlphaFold 3 (search) AI to identify OPG153 (search), a previously unconsidered viral surface protein, as a promising target for monkeypox virus (search) vaccines and antibody therapies.
The breakthrough emerged from reverse vaccinology, analyzing antibodies from mpox (search) survivors to predict which of 35 viral surface proteins they bind to most effectively.
Mouse studies demonstrated that injection with the AI-recommended viral protein produced neutralizing antibodies against MPXV, suggesting potential for simpler and cheaper vaccine development.
An international research team has leveraged artificial intelligence to identify a novel drug target for combating monkeypox virus (search) (MPXV), marking the first major breakthrough toward more effective treatments for the disease that poses particular risks to children, pregnant women, and immunocompromised individuals.
Published in Science Translational Medicine, the study demonstrates that mice injected with a viral surface protein identified through AI analysis produced antibodies capable of neutralizing MPXV. This discovery opens pathways for developing new vaccines and antibody therapies against mpox (search), the disease caused by MPXV.
AI-Driven Target Identification
The breakthrough began with Italian researchers who identified 12 antibodies from the blood of patients previously infected with MPXV or vaccinated against it. These antibodies effectively neutralized the virus, but their specific viral targets remained unknown. The University of Texas at Austin team employed AlphaFold 3 (search) AI to predict which of approximately 35 viral surface proteins these antibodies bind to most strongly.
"It would have taken years to find this target without AI," said Jason McLellan, professor of molecular biosciences at UT Austin and co-lead author of the study. "It was really exciting because no one had ever considered this protein before for vaccine or antibody development. It had never been shown to be a target of neutralizing antibodies."
The AI model predicted with high confidence that certain antibodies would bind to a viral surface protein called OPG153 (search), a prediction subsequently verified through follow-up experiments. This protein represents a promising target for developing new antibody therapies and vaccines.
Reverse Vaccinology Approach
McLellan's team employed what he terms "reverse vaccinology" to make this discovery. "We started with people who survived infection with monkeypox virus (search), isolated antibodies that they naturally produced and worked backward to find what part of the virus acted as the antigen for those antibodies. Then we engineered the antigen to elicit similar antibodies in mice," McLellan explained.
This approach offers significant advantages over traditional vaccine development. "Unlike a whole-virus vaccine that's big and complicated to produce, our innovation is just a single protein that's easy to make," McLellan noted.
Clinical Context and Implications
The 2022 mpox (search) outbreak affected more than 150,000 people worldwide, causing flu-like symptoms, painful rashes and lesions, and nearly 500 deaths. Current vaccines, repurposed from smallpox (search) prevention efforts, are complicated and costly to manufacture due to their use of whole, weakened viruses.
Given MPXV's close relationship to the smallpox (search) virus, this discovery could potentially lead to improved vaccines and therapies for smallpox, which poses significant bioterrorism risks due to its easy transmission and high mortality rates.
Development Pipeline
The research team is now developing optimized versions of vaccine antigens and antibodies that are more effective at fighting disease while being cheaper and easier to produce than existing whole-virus vaccines. The ultimate goal is testing vaccine antigens and antibody therapies in humans for protection against both mpox (search) and smallpox (search).
UT Austin has filed a patent application for the use of OPG153 (search) and its derivatives as vaccine antigens, while the Fondazione Biotecnopolo di Siena (search) has filed for patents on antibodies targeting OPG153.
The study's co-authors include Emily Rundlet, Ling Zhou, and Connor Mullins from UT Austin, along with Rino Rappuoli and Emanuele Andreano from the Fondazione Biotecnopolo di Siena (search) in Italy. The research received partial funding from the Welch Foundation.