TY - JOUR
T1 - Broad spectrum antiviral BDGR-164 provides protection against lethal neurotropic alphavirus infection in mice
AU - Williams, Evan P.
AU - Xue, Yi
AU - Yang, Dong
AU - Lee, Jasper
AU - Kim, Eunjung
AU - Ponce-Flores, Alexander
AU - Zalduondo, Lillian
AU - Cao, Xufeng
AU - Chung, Donghoon
AU - Golden, Jennifer E.
AU - Meibohm, Bernd
AU - Fitzpatrick, Elizabeth A.
AU - Weaver, Scott C.
AU - Jonsson, Colleen B.
N1 - Publisher Copyright:
© 2025 The Authors
PY - 2025/8
Y1 - 2025/8
N2 - 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.
AB - 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.
KW - Antiviral
KW - BALB/c mice
KW - BDGR-164
KW - Broad-spectrum
KW - Neurotropic alphaviruses
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U2 - 10.1016/j.antiviral.2025.106206
DO - 10.1016/j.antiviral.2025.106206
M3 - Article
AN - SCOPUS:105007057887
SN - 0166-3542
VL - 240
JO - Antiviral research
JF - Antiviral research
M1 - 106206
ER -