# Understanding the Protein-Protein Interactions Important for the Initiation of HSV-1 DNA Synthesis

> **NIH NIH F30** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2020 · $50,520

## Abstract

PROJECT SUMMARY/ABSTRACT
Herpes Simplex Viruses type 1 (HSV-1) is important human pathogen that can cause a wide range of
pathologies ranging from the common cold sore to disseminated end-organ disease. HSV-1 poses a significant
public health due to the rise of acyclovir resistance, particularly within the ever-increasing
immunocompromised patient population. It is therefore of great interest to develop new potential therapies
against these viruses. Initiation, or the unwinding of dsDNA at the origin of replication, is the first step required
for viral DNA synthesis. Initiation is therefore a rate-limiting step during HSV-1 DNA replication and may be a
good target for the development of new antivirals. Two viral proteins are known to be essential for initiation: the
origin binding protein UL9 and the single-stranded DNA binding protein ICP8. Despite the importance of this
process, we still lack a detailed understanding of the molecular mechanisms and protein-protein interactions
that drive initiation. In this proposal, we aim to examine how protein-protein interactions between ICP8
and UL9 contribute to initiation by mapping the residues on both ICP8 and UL9 essential for this
interaction and by examining their importance in the context of infection. The C-terminal 27 amino acids
of UL9 are essential for ICP8 interaction and for the initiation of origin-dependent DNA synthesis. Within this
region, there is a conserved stretch of amino acids that form a linear motif (VNF, a.a. 846-848) that has been
suggested to be essential for ICP8-UL9 interaction and recruitment of ICP8 to the origin. Aim 1 will test the
hypothesis that this VNF motif is essential for origin unwinding and origin-dependent DNA synthesis in
the context of infection. Although the region of UL9 important ICP8-UL9 is known, the reciprocal site on ICP8
that is essential for this interaction has not yet been identified. Interestingly the VNF motif that is thought to be
important for UL9-ICP8 interaction has sequence similarity to a linear motif (FNF, a.a. 1142-1144) in the C-
terminus of ICP8 that is important for ICP8 self-interaction. Our lab recently published data to support the
notion that the FNF motif mediates ICP8 self-interaction by docking onto a conserved hydrophobic pocket on a
neighboring molecule of ICP8. We hypothesize that the VNF motif in the C-terminus of UL9 may dock into
the same conserved hydrophobic pocket on ICP8. We have recently shown that the C-terminus of UL9 fails
to bind to a mutant version of ICP8 in which this hydrophobic pocket has been disrupted. Aim 2 of this
proposal will build on these preliminary data. Knowledge gained from the experiments in this proposal will
not only inform our model as to how initiation occurs, but may also pave the way for the development of new
antiviral compounds that can target and disrupt this essential step during HSV-1 infection. This work will allow
me to take advantage of training opportunities and mentorship to advanc...

## Key facts

- **NIH application ID:** 9948479
- **Project number:** 5F30AI143125-02
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Katherine DiScipio
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2019-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948479

## Citation

> US National Institutes of Health, RePORTER application 9948479, Understanding the Protein-Protein Interactions Important for the Initiation of HSV-1 DNA Synthesis (5F30AI143125-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9948479. Licensed CC0.

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