Williams Evan P, Xue Yi, Yang Dong, Lee Jasper, Kim Eunjung, Ponce-Flores Alexander, Zalduondo Lillian, Cao Xufeng, Chung Donghoon, Golden Jennifer E, Meibohm Bernd, Fitzpatrick Elizabeth A, Weaver Scott C, Jonsson Colleen B
Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, United States of America.
Regional Biocontainment Laboratory, University of Tennessee Health Science Center, Memphis, TN, United States of America.
Antiviral Res. 2025 Aug;240:106206. doi: 10.1016/j.antiviral.2025.106206. Epub 2025 May 31.
The New World alphaviruses, eastern equine encephalitis virus (EEEV), Venezuelan equine encephalitis virus (VEEV), and western equine encephalitis virus (WEEV), cause febrile illness that can progress to fatal disease in humans and equids. As there are no therapeutics approved for the treatment of neurotropic alphavirus disease in humans, we report a structurally novel, quinazolinone, BDGR-164, with nanomolar potency against VEEV, EEEV, and WEEV. Using an intranasal route of virus infection in a lethal BALB/c model, to model aerosol infection in a biodefense scenario, prophylactic subcutaneous administration of BDGR-164 conferred 100 % (VEEV), 88 % (EEEV), and 63 % survival (WEEV) compared to uniform lethality in sham-treated animals. Using RNA-Seq and histopathology, we determined that viral RNA levels and antigen were reduced significantly in the brains of mice from the virus-infected, BDGR-164-treated group as compared to virus-infected, sham-treated group. Moreover, there was a significant reduction in the virus-infected, BDGR-164-treated mice in their host immune responses associated with inflammatory signaling, immune cell recruitment, and programmed cell death. Comparison of cytokines in sera from VEEV-, EEEV- or WEEV-infected mice with and without BDGR-164-treatment suggested that lower levels of IL-6, TNF-α, and RANTES levels correlated with protection and may serve as useful early biomarkers in treatment studies in animal models. In conclusion, our studies show broad and potent prophylactic efficacy of BDGR-164 against neurotropic alphaviruses.
新大陆甲病毒，如东部马脑炎病毒（EEEV）、委内瑞拉马脑炎病毒（VEEV）和西部马脑炎病毒（WEEV），可引起发热性疾病，在人类和马科动物中可能发展为致命疾病。由于目前尚无获批用于治疗人类嗜神经性甲病毒疾病的疗法，我们报告了一种结构新颖的喹唑啉酮类化合物BDGR-164，它对VEEV、EEEV和WEEV具有纳摩尔级别的效力。在致死性BALB/c模型中采用鼻内病毒感染途径，以模拟生物防御场景中的气溶胶感染，与假处理动物的全部死亡相比，预防性皮下注射BDGR-164可使VEEV感染组的存活率达到100%，EEEV感染组为88%，WEEV感染组为63%。通过RNA测序和组织病理学，我们确定与病毒感染的假处理组相比，病毒感染的BDGR-164处理组小鼠大脑中的病毒RNA水平和抗原显著降低。此外，在病毒感染的BDGR-164处理小鼠中，与炎症信号传导、免疫细胞募集和程序性细胞死亡相关的宿主免疫反应也显著降低。对有或没有BDGR-164处理的VEEV、EEEV或WEEV感染小鼠血清中的细胞因子进行比较表明，较低水平的IL-6、TNF-α和RANTES水平与保护作用相关，可能作为动物模型治疗研究中有用的早期生物标志物。总之，我们的研究表明BDGR-164对嗜神经性甲病毒具有广泛而有效的预防作用。
