New Drug Found To Be Effective Against Encephalitis Viruses

A novel antiviral drug developed and manufactured by University of Wisconsin-Madison School of Pharmacy researchers is very efficient in mice against two types of lethal encephalitis viruses. The molecule, known as BDGR-49, was produced by UW-Madison researchers in collaboration with cellular virologists at the University of Louisville and animal efficacy trials at the University of Tennessee Health Science Center. The researchers discovered that BDGR-49 protects mice afflicted with the fatal eastern equine encephalitis virus (EEEV) or Venezuelan equine encephalitis virus (VEEV). In a publication published April 12 in Science Translational Medicine, the researchers described BDGR-49 and its efficacy against deadly EEEV or VEEV infections in mice models.

“Collaboration across disciplines and capabilities was key to this discovery,” says Jennifer E. Golden, a UW–Madison professor of pharmacy and synthetic medicinal chemist who led the discovery and optimization effort. Colleen Jonsson, professor at UTHSC, tested the compound in mice. Donghoon Chung, a professor of microbiology and immunology at Louisville’s Center for Predictive Medicine, performed further virology studies.

The researchers discovered that BDGR-49 suppressed EEEV and VEEV well and was well tolerated in mice. The chemical gave considerable protection to animals infected with EEEV. Meanwhile, it not only completely protected VEEV-infected mice, but it could also be employed as a therapeutic treatment days later.

“We had been working on a different compound structure for years,” says Golden. “Compounds that emerged from that earlier work were pivotal to understanding how to construct a better antiviral compound class that works well against VEEV and EEEV—ultimately providing a roadmap to the design and discovery of BDGR-49.”

This antiviral compound’s capacity to enter the brain, where viruses inflict damage, is an essential trait, as are its improved stability, potency, and efficacy compared to prior prototypes created by Golden and her colleagues. According to resistance tests, BDGR-49 effectively prevents these viruses from replicating themselves, implying that it works by interfering with the viral machinery required for replication.
Equine encephalitis viruses, which are classified as New World alphaviruses, are transmitted by mosquito bites and can infect the brain, causing neurological damage, major sickness, and death in both humans and horses. There are currently no FDA-approved vaccinations or therapies for preventing or treating alphavirus infection in humans.

EEEV infection symptoms include fever, headache, chills, and vomiting. Seizures, comas, and death can all result from a severe infection. One-third of those who get encephalitis (brain inflammation) from EEEV infection die, and many of those who survive have long-term neurological sequelae.
Although outbreaks of eastern equine encephalitis are uncommon in the United States, with an average of 11 cases per year, an outbreak in nine states in 2019 resulted in 38 confirmed cases, 19 deaths, and neurological consequences in survivors.
Although Venezuelan equine encephalitis has a significantly lower mortality rate of 1%, outbreaks can infect thousands of humans, with the majority of cases happening in Central and South America. While insect bites are the most common source of these diseases, there is also concern that the viruses could spread to humans and be used as bio-weapons.

For more than a decade, the team has been designing and optimizing chemical structures against VEEV and EEEV. Golden, Jonsson, and Chung are co-investigators at the UTHSC-based Center of Excellence for Encephalitic Alphavirus Therapeutics. The center was established to improve the characteristics and activity of early-stage small molecule drugs discovered in the Golden lab, with the goal of developing them into clinical candidates for VEEV and EEEV that could be evaluated in humans.

There are no approved prophylactic or therapeutic options in our arsenal for any human alphavirus infection, so our goal is to develop a drug against VEEV and EEEV that is safe and effective in humans,” Golden says. “While there is still much work to be done, the discovery of BDGR-49 is a remarkable achievement in reaching that goal based on the compound’s drug-like characteristics and ability to prevent animals from dying from these infections.”

The researchers are testing BDGR-49 in advanced preclinical investigations to learn more about its antiviral properties. Because RNA viruses like EEEV and VEEV are prone to mutation, they can rapidly evolve into more fatal or transmissible forms, resulting in widespread epidemics.

“It is essential that we develop these countermeasures for viruses of pandemic potential so we don’t find ourselves unprepared to respond to an outbreak,” Golden says. “We can do better, and we intend to leverage this discovery as broadly as possible with respect to VEEV, EEEV, and other viruses of concern.”

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