Identifying Antiviral Peptides to Inhibit HSV-1 Replication Público

Abstract

Herpes Simplex Virus-1 (HSV-1) is a neurotropic virus that establishes lifelong latency

in the trigeminal ganglia, periodically reactivating to cause neuronal damage and symptomatic

outbreaks. Currently, there is no cure or universal vaccine, and available antivirals are

suboptimal. Therefore, we need novel prophylactic and therapeutic targets. One such target is

herpesvirus nuclear egress, , an essential process in which the Nuclear Egress Complex (NEC),

composed of UL31 and UL34, facilitates capsid transport across the nuclear envelope. The NEC

oligomerizes on the nuclear membrane, binds to egressing capsids, and deforms the membrane to

facilitate nuclear exit. Herein, we generated self-mimicking peptides intended to prevent NEC

oligomerization, an essential aspect of NEC function. We screened the peptides for interactions

with the NEC using biolayer interferometry and co-sedimentation assays. We identified one

peptide that disrupted NEC heterodimer formation while others did not prevent the NEC from

binding membranes, suggesting peptides likely perturb NEC oligomerization and not

NEC/membrane associations. Future studies should explore peptide effects on NEC

oligomerization, chemical crosslinking, optimize inhibitory design, and assess antiviral potential

in neuronal models. Understanding how NEC-targeting peptides modulate HSV-1 replication

may inform novel approaches to mitigating HSV-1-induced neurodegeneration and advancing

antiviral strategies with potential applications for other neurotropic viruses.

Table of Contents

Abstract........................................................................................................................................... 1

Background and Introduction......................................................................................................... 2

Methodology................................................................................................................................... 5

Results............................................................................................................................................. 7

Discussion..................................................................................................................................... 12

Tables and Figures........................................................................................................................ 15

Figure 1. Mechanism of nuclear egress.............................................................................15

Table 1. Sequences of Peptides Derived from UL31 or UL34 Screened via

BLI……………………………………………………………………...………………..16

Table 2. Potential inhibitory peptides and protein origins…………………...……...…...16

Figure 2. 3D structure of the NEC and side views of three identified membrane-

interacting peptides………………………………………………...……………….……17

Figure 3. Example BLI screening conducted on truncated construct NEC∆140-

190………………………………………………………………………………………..18

Figure 4. Structure of 6-FAM tag…………………...………………...…………………19

Figure 5. Quantification of pellet signal intensity for NEC 220 and Peptide 1-6-FAM

across different experimental conditions……………………..………………………….19

Figure 6. Peptide 1-6-FAM assays run on Tris/Tricine gels………………………..……21

Figure 7. Pellet and Supernatant Signal Intensities for Peptide 2-6-FAM at 10X

Concentration…………………………………………………………………...………..22

Figure 8. Initial assay conducted with peptide 2-6-FAM…..………………………....…23

Figure 9. Peptide 3-6-FAM assessed at 1X, 2X, and 10X concentrations…………....….23

Figure 10. Pellet and Supernatant Signal Intensities for Peptide 4-6-FAM at 10X

Concentration….………………………………………………………………..………..24

Figure 11. Pellet and Supernatant Signal Intensities for Peptide 1 (Untagged) at 10X

Concentration………………………………………………………………………….....25

Figure 12. Pellet and Supernatant Signal Intensities for Peptide 2 (Untagged) at 10X

Concentration……………………………………………………………...……………..26

Figure 13. Peptide 3 (untagged) assessed at 1X, 2X, and 10X concentrations…..........…27

Figure 14. Pellet and Supernatant Signal Intensities for Peptide 3 (Untagged) at 10X

Concentration………………………………………………………………………....….28

Figure 15. Pellet and Supernatant Signal Intensities for Peptide 4 (Untagged) at 10X

Concentration……………………………………………………………………….....…29

Figure 16. Quantification of pellet signal intensity for NEC 220 with Peptide 5 lacking

the 6-FAM tag………………………………………………………………………....…30

Figure 17. Peptides 1-5 6-FAM in solution with Laemmli buffer………………….…....30

References..................................................................................................................................... 31

About this Honors Thesis

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School	Emory College
Department	Neuroscience and Behavioral Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Chemistry, Biochemistry Biology, Virology Biology, Neuroscience
Palavra-chave	Neuroscience HSV-1 Biochemistry Neurotropic Viruses
Committee Chair / Thesis Advisor	Dr. Elizabeth Bennett Draganova, Emory University
Committee Members	Dr. Tyler Beyett, Emory University Dr. Leah Roesch, Emory University

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