Structure-Based Discovery of Lead Compounds to Prevent Neuronal Death in Venezuelan Equine Encephalitis Virus Infection

Abstract

The Venezuelan Equine Encephalitis Virus (VEEV) is a positive, single-stranded RNA virus that causes severe neuronal damage by disrupting nuclear-cytoplasmic transport. The virus crosses the blood-brain barrier and produces the VEEV capsid protein. The N-terminus of the capsid, the H68 peptide, contains nuclear localization signals (NLS) and nuclear export signals (NES). These conflicting signals promote formation of a tetrameric complex involving the nuclear import protein, importin alpha (ImpA), and the nuclear export protein, CRM1. This complex then blocks the nuclear pores, ultimately leading to neuronal death. Previous studies found compounds that prevent nuclear pore blocking but also suffer from limited efficacy and potential off-target toxicity. We leveraged models of the tetrameric complex to apply structure-based drug design with pharmacophores to discover and evaluate candidate compounds based on their physical features, such as binding sites and contact residues. We will present some of the chemotypes found as well as the rationale for why we believe they offer better starting points than the current chemical leads.