Synthesis of Inhibitors of the Impα Protein Binding as a Potential Treatment for Venezuelan Equine Encephalitis Virus (VEEV) infection Binding

Abstract

Venezuelan Equine Encephalitis Virus (VEEV) is a mosquito-borne pathogen that commonly infects equines but has transmitted to humans in certain cases. The lack of small molecule antivirals for treatment against VEEV prompted an in silico high throughput screen (HTS), which led to a hit molecule named DP9. A series of DP9 analogues were synthesized using a two-step reaction protocol starting from a condensation reaction with hippuric acid followed by amidation of the resulting lactone adduct. Preliminary results led us to keep select portions of DP9 fixed while we modified the "tail" region by using different amine nucleophiles. A diverse series of 14 DP9 analogues were synthesized in yields ranging from 50-100% and fully characterized by ¹H and ¹³C NMR and ESI-MS. The modulation of amine tails explores different physiochemical properties of the “tail” region by incorporating different lengths, sizes, types of aromatic rings, and basic amines groups. DP9 analogues inhibitory activity against VEEV were quantified using an AlphaScreen assay to show inhibition of the an NLS-sequence peptide binding to the Impα protein.