Brain-penetrating drug candidate effective against deadly encephalitis viruses

University of Louisville researcher Donghoon Chung and collaborators have designed, synthesized and tested a new antiviral compound and shown it to be highly effective against two types of encephalitis viruses that cause devastating illness in humans. In preclinical studies, the team found that BDGR-49 protects against deadly eastern equine encephalitis virus (EEEV) or Venezuelan equine encephalitis virus (VEEV).

Chung, associate professor in the UofL Department of Microbiology and Immunology and the Center for Predictive Medicine, and colleagues at the University of Wisconsin–Madison’s School of Pharmacy and the University of Tennessee Health Sciences Center (UTHSC) described their work with BDGR-49 in a study published April 12 in Science Translational Medicine.

Chung led chemical virology studies, Jennifer E. Golden, associate professor in the UW–Madison School of Pharmacy and synthetic medicinal chemist, led the discovery and optimization effort and Colleen Jonsson, a professor at UTHSC, performed animal efficacy studies.

The team found that BDGR-49 potently inhibited EEEV and VEEV and was well tolerated. The compound provided significant protection to EEEV-infected animals. Meanwhile, it not only fully protected VEEV-infected animals, but could also be used as a therapeutic treatment days after infection.

An important feature of this antiviral compound is its ability to access the brain where these viruses cause damage, while other critical attributes include its improved stability, potency and efficacy compared to earlier prototypes. Based on resistance studies, BDGR-49 efficiently prevents these viruses from copying themselves, meaning it operates by disrupting the viral machinery needed for replication. 

Classified as New World alphaviruses, equine encephalitis viruses are transmitted by the bite of a mosquito and can infect the brain, causing neurological effects, serious illness and death in humans as well as horses. There currently are no FDA-approved vaccines or treatments available specifically for preventing or treating alphavirus infection in humans.

Symptoms of EEEV infection include fever, headache, chills and vomiting. Severe infection can result in seizure, coma and death. About one-third of individuals who develop encephalitis (brain inflammation) from EEEV infection die, and many of those who do recover suffer permanent neurological effects.

Although outbreaks of eastern equine encephalitis (EEE) are rare, with an average of 11 cases per year in the United States, a 2019 outbreak of EEE across nine states resulted in 38 confirmed cases, 19 deaths and neurological effects in survivors.

VEE has a much lower mortality rate of 1%, but outbreaks can affect thousands of people, most often occurring in Central and South America. While insect bites are the typical cause of these infections, there is also concern the viruses could be leveraged as bioweapons.

“What we are trying to do is to develop a drug that can be used to treat infected people or as a prophylactic in case of bioterrorism,” Chung said. “Now we are seeing that it protects from lethal infection. This is a big milestone in terms of the therapeutic development.”

Chung, Golden and Jonsson have been developing chemical structures against VEEV and EEEV for more than a decade. They are co-investigators in the Center of Excellence for Encephalitic Alphavirus Therapeutics, based at UTHSC. The center was created to refine the properties and activity of early-stage small molecule compounds discovered in the Golden lab and to develop them into clinical candidates for VEEV and EEEV that could be studied in humans. This work received a five-year, $21-million grant from the National Institutes of Health in 2019.

The team now is evaluating BDGR-49 in advanced preclinical studies and expanding the understanding of its antiviral properties. As RNA viruses such as EEEV and VEEV are prone to develop mutations, they can potentially evolve into more lethal or transmissible versions without warning, resulting in widespread infections.

“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.”

This research was supported by the National Institute of Allergy and Infectious Diseases (U19AI142762 and R01AI118814) and by a grant (S10OD016226) from the Office of the Director of the NIH.