The antiviral BDGR-49 provides protection from lethal, neurotropic Venezuelan equine encephalitis virus intranasal infection in mice

Venezuelan, western, and eastern equine encephalitis virus (VEEV, WEEV, and EEEV) cause a febrile illness that may result in fatal neurological disease in humans and equines. Human infections are typically from mosquito bites, although cases from respiratory exposure in laboratory accidents have been documented. In addition to natural mosquito-borne infection, the potential biothreat inherent in the ability to disseminate these viruses via the respiratory route has driven the development of antiviral drugs for this route of exposure. To address this gap, we tested the prophylactic administration of a novel brain-penetrant, antiviral, BDGR-49, against a lethal intranasal challenge of VEEV, WEEV, or EEEV in BALB/c mouse model. BDGR-49 conferred 100% protection with 6 mg kg^-1 twice per day for 6 days for VEEV, but not EEEV or WEEV. By 8 days post-infection (dpi), infectious virus, viral RNA, and viral antigen in the brain of BDGR-49-treated mice were significantly reduced. Brains of VEEV TrD-infected, BDGR-49-treated mice showed a significant reduction in the expression of genes associated with inflammation (<i>IFNB1</i>, <i>TNF</i>, <i>IL6</i>, and <i>CCL5</i>) and cell death (<i>CASP4</i>, <i>GSDMD</i>, <i>PYCARD</i>, and <i>ZBP1</i>). At dpi 14, histopathology showed that neuronal lesions and inflammatory cell infiltrates were essentially absent, and viral antigen was not detected in the brains of VEEV TrD-infected, BDGR-49-treated mice. In summary, although BDGR-49 treatment showed significant promise for the treatment of mice exposed intranasally to VEEV, the more rapid and efficient entry of EEEV and WEEV by this route into the central nervous system will require additional optimization of the dosing regimen.IMPORTANCEProphylactic and therapeutic treatment of viruses that cause encephalitis requires fast-acting drugs that rapidly penetrate the blood-brain barrier. Currently, clinicians have only a limited set of antivirals for the treatment of neurotropic infections such as herpesviruses or HIV-1, and none for alphaviruses, and treatment outcomes remain poor. New medical countermeasures will address the gap in treatment of viral encephalitis such as those caused by the neurotropic alphaviruses and others.