Broad spectrum efficacy of BDGR-164 against neurotropic alphaviruses and correlates of protection
Infections by 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. Currently there are no FDA-approved antivirals for prophylactic or therapeutic treatment of human infection by these viruses. To combat these infections, we have developed a novel small molecule, BDGR-164, which has subnanomolar potency against VEEV, EEEV, and WEEV.  Using an intranasal route of virus infection in a lethal BALB/c model, prophylactic subcutaneous administration of BDGR-164 conferred 100% (VEEV), 88% (EEEV), and 63% (WEEV) survival. To evaluate the ability of BDGR-164 to reduce viral RNA/antigen, inflammation, and pathogenesis, we used RNASeq and histopathology of whole brain at 4 days post-infection (dpi). Viral RNA levels and antigen were reduced significantly in virus-infected and BDGR-164-treated versus virus-infected, sham-treated mice. Moreover, there was a significant reduction in host immune responses associated with inflammatory signaling, immune cell recruitment, and programmed cell death in virus-infected, BDGR-164 treated mice. Cytokine analyses of sera corroborated the reduction in upregulation of the immune response in virus-infected, BDGR-164 treated mice. Limited antiviral resistance to BDGR-164 was detected in one mouse on 4 dpi at NSP2:Y102C. In conclusion, our studies suggest that BDGR-164 has broad and potent prophylactic efficacy against the neurotropic alphaviruses. Overall design: BALB/c mice were either intranasally mock-infected or infected with Eastern equine encephalitis virus  (EEEV), Venezuelan equine encephalitis virus  (VEEV), or Western equine encephalitis virus (WEEV) prophylactically treated with BDGR-164 or sham-treated. At 4 days post-infection mice were euthanized and brains collected and RNA-Seq performed on.