Mosquito-borne viruses (arboviruses) represent an emergent public health threat largely due to the widespread prevalence of mosquitoes. Among these viruses, the equine encephalitis viruses are of particular interest to our lab because they are debilitating and potentially weaponizable infectors of the central nervous system (CNS). This is particularly troublesome because of the absence of effective human vaccines and therapeutics for these viruses. We are therefore interested in the development and optimization of novel small-molecule antivirals, using both a Western equine encephalitis virus (WEEV) replicon assay and live virus. We explored structural modifications of the previously reported indole-based CCG-205432 (WEEV replicon IC50 = 0.53 � 0.1 �M) in an effort to improve physicochemical properties predictive of successful CNS drugs, as well as to establish essential pharmacophore features and reduce P-glycoprotein (Pgp) interaction. Our investigations revealed the importance of the secondary amide to antiviral activity and demonstrated a dependence of Pgp interaction on both molecular weight and conformation.

Development of novel small molecule antivirals for Western equine encephalitis virus

247th National Meeting (2014)

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