Efficacy of a brain-penetrant antiviral in lethal Venezuelan and eastern equine encephalitis mouse models

Venezuelan and eastern equine encephalitis viruses (VEEV and EEEV, respectively) are mosquito-borne, neuro-invasive human pathogens for which no FDA-approved therapeutic exists. Besides the biothreat posed by these viruses when aerosolized, arthropod transmission presents serious health risks to humans, as demonstrated by the 2019 outbreak of EEE disease in the United States that resulted in 38 confirmed cases, 19 deaths, and neu-rological effects in survivors. Here, we describe the discovery of a 2-pyrrolidinoquinazolinone scaffold, efficient-ly synthesized in two to five steps, whose structural optimization resulted in profound antiviral activity. The lead quinazolinone, BDGR-49, potently reduced cellular VEEV and EEEV titers by >7 log at 1 mu M and exhibited suit-able intravenous and oral pharmacokinetic profiles in BALB/c mice to achieve excellent brain exposure. Out-standing in vivo efficacy was observed in several lethal, subcutaneous infection mouse models using an 8 -day dosing regimen. Prophylactically administered BDGR-49 at 25 mg kg-1 per day fully protected against a 10x LD50 VEEV Trinidad donkey (TrD) challenge in BALB/c mice. Similarly, we observed 70% protection when 10x LD50 EEEV FL93-939-infected C57BL/6 mice were treated prophylactically with BDGR-49 at 50 mg kg-1 per day. Last, we observed 100% therapeutic efficacy when mice, challenged with 10x LD50 VEEV TrD, were dosed at 48 hours after infection with BDGR-49 at 25 mg kg-1 per day. Mouse brain viral titers at 96 hours after infection were reduced to values near the limit of detection. Collectively, these results underscore the substantial devel-opment potential of a well-tolerated, brain-penetrant lead compound that shows promise in preventing and treating encephalitic alphavirus disease.

Automated summary

Researchers have discovered a compound, BDGR-49, that exhibits potent antiviral activity against Venezuelan and eastern equine encephalitis viruses. The compound showed excellent efficacy in mouse models and has the potential for development as a treatment for encephalitic alphavirus disease.