Research Project
10052570
ABSTRACT Venezuelan equine encephalitic virus (VEEV) infects humans and is classified as a Category B pathogen by NIAID due to its easy dissemination. In humans, VEEV infection can result in inflammation, acute degenerative neuronal changes, behavioral changes, memory loss and seizures, with severe cases resulting in death. There is currently no antiviral therapeutic treatment for patients infected with VEEV. The live attenuated vaccine TC83 can protect against VEEV infection, but due to a high frequency of adverse side effects, its use is limited to military and at-risk laboratory personnel. Therefore, the discovery of new therapeutics is urgently needed. VEEV is able to suppress host transcription by blocking cellular nuclear trafficking at least partially due to its capsid protein forming a complex with the host proteins importin?/? (Imp?/?1) and CRM1. Mutation of the nuclear localization sequence (NLS) of capsid results in loss of viral virulence, indicating that the ability of capsid to enter the nucleus is critical for VEEV pathogenesis and a viable target for antiviral therapeutic development. We hypothesize that small molecule inhibitors that interfere with capsid-Imp? protein-protein interaction (PPI) will prevent VEEV induced pathologies. We have identified two novel small molecules, 1111684 and G281-1485, which disrupt the ability of VEEV capsid to interact with Imp?, leading to altered capsid localization, decreased viral replication and increased survival of the host cell. Here we propose to design and synthesize second- generation capsid-Imp? PPI inhibitors with improved potency and bioavailability. To this end, we proposed 4 interlinked aims: Aim 1: In silico design of second-generation capsid-Imp? inhibitors; Aim 2: Synthesis and biochemical characterization of second generation capsid-Imp? inhibitors; Aim 3: Determine the in vitro selectivity index and bioavailability of capsid:Imp? inhibitors; and Aim 4: Determine the PK/PD/Tox of capsid:Imp? inhibitors. The new knowledge gained from our study will be applicable to wide-range applications involving capsid-Imp? interactions including HSV-1 or eastern and western equine encephalitic viruses.
