# Mechanisms of Conformational Dynamics and Inhibition of the HSV-1 Nuclear Egress Complex

> **NIH NIH K99** · TUFTS UNIVERSITY BOSTON · 2022 · $44,132

## Abstract

Project Summary/Abstract
Herpesviruses are double-stranded DNA viruses that infect almost all mammals, including humans, making them
highly effective pathogens. A hallmark event in the herpesvirus replication cycle requires immature capsids to
bud through the inner nuclear membrane (INM) to the perinuclear space in a process termed nuclear egress.
This essential first step in viral exit is mediated by the conserved viral nuclear egress complex (NEC) and is the
focus of this proposal. The ability of the NEC to oligomerize on membranes is important for capsid budding, yet
the conformational changes undergone to perform this are unknown. The long-term goal of this research is to
determine how disruption of NEC oligomerization perturbs conformational changes that drive budding (Aim 1)
and develop peptide-based screening platforms for identifying novel NEC inhibitors (Aim 2). This work stems
from a central hypothesis, formulated from substantial preliminary data, that the NEC can be inhibited,
specifically by perturbing NEC oligomerization. The scientific premise of this work is to formulate a detailed
mechanism of herpesvirus nuclear egress to inform the design of innovative therapeutic compounds. A
combination of cutting-edge biophysical techniques, including cryoelectron microscopy/tomography (cryoEM/T),
along with mutational and functional approaches will be used to identify the molecular interactions undergone by
Herpes Simplex NEC during budding and to identify routes for inhibiting this process. The K99 phase of this
proposal is structured to not only answer these fundamental questions surrounding herpesvirus nuclear egress
but also provide a platform for transitioning to an independent research career centered around identifying
small molecule and peptide inhibitors targeting specific protein-protein interactions occurring at various stages
of herpesviral replication. This type of protein targeting will provide a novel means for determining specific protein
function within the virus and expand the repertoire of therapeutic targets available for the treatment of this
disease. Focus during this phase will be on fine-tuning expertise in cryoEM/T by investigating NEC mutants
designed to perturb oligomerization (in collaboration with cryoEM/T expert Dr. Zhiheng Yu at the HHMI Janelia
Research Campus), gain instruction in virological techniques to perform functional studies on NEC mutants (in
collaboration with herpes biology experts Dr. Richard Roller at the University of Iowa and Dr. David Knipe at
Harvard Medical School) and establish peptide screening platforms (under advisement from Dr. Joshua Kritzer
at Tufts University – an expert in therapeutic peptide design). Under the guidance of an extremely qualified
mentor (Dr. Katya Heldwein – an expert in structural virology) and co-mentor (Dr. Ralph Isberg – an expert in
postdoctoral training for successful academic careers), within the supportive institutional environment of Tufts
University, this ...

## Key facts

- **NIH application ID:** 10460586
- **Project number:** 5K99AI151891-02
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Elizabeth Bennett Draganova
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $44,132
- **Award type:** 5
- **Project period:** 2021-08-03 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10460586

## Citation

> US National Institutes of Health, RePORTER application 10460586, Mechanisms of Conformational Dynamics and Inhibition of the HSV-1 Nuclear Egress Complex (5K99AI151891-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10460586. Licensed CC0.

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