# Developing capsid-importin alpha inhibitors for the treatment of VEEV infection

> **NIH NIH R01** · GEORGE MASON UNIVERSITY · 2021 · $718,061

## Abstract

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 importinα/β (Impα/β1) 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-Impα 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 Impα, 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-Impα PPI inhibitors with improved potency and bioavailability. To this end, we proposed 4
interlinked aims: Aim 1: In silico design of second-generation capsid-Impα inhibitors; Aim 2: Synthesis and
biochemical characterization of second generation capsid-Impα inhibitors; Aim 3: Determine the in vitro
selectivity index and bioavailability of capsid:Impα inhibitors; and Aim 4: Determine the PK/PD/Tox of
capsid:Impα inhibitors. The new knowledge gained from our study will be applicable to wide-range applications
involving capsid-Impα interactions including HSV-1 or eastern and western equine encephalitic viruses.

## Key facts

- **NIH application ID:** 10263364
- **Project number:** 5R01AI143817-02
- **Recipient organization:** GEORGE MASON UNIVERSITY
- **Principal Investigator:** DMITRI Konstantinovich KLIMOV
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $718,061
- **Award type:** 5
- **Project period:** 2020-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10263364

## Citation

> US National Institutes of Health, RePORTER application 10263364, Developing capsid-importin alpha inhibitors for the treatment of VEEV infection (5R01AI143817-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10263364. Licensed CC0.

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