Document Type

Honors Capstone Project

Date of Submission

Spring 5-1-2014

Capstone Advisor

Dr. Jennifer Moffat

Honors Reader

Dr. Kari Segraves

Capstone Major

Biology

Capstone College

Arts and Science

Audio/Visual Component

no

Capstone Prize Winner

no

Won Capstone Funding

yes

Honors Categories

Sciences and Engineering

Subject Categories

Biology | Other Microbiology | Virology

Abstract

The alphaherpesvirus that causes chicken pox and shingles, varicella-zoster virus (VZV), infects skin fibroblasts and keratinocytes. These cells are typically quiescent and it is known that VZV manipulates their intracellular environment to activate MAPK signaling cascades, cell cycle regulators, and many transcription factors for its replication. We hypothesized that inhibition of cell kinases would prevent VZV replication and also elucidate which pathways are most important. We evaluated 80 kinase inhibitors for cytotoxicity and anti-proliferative effects on human foreskin fibroblasts, and then determined their antiviral efficacy against VZV-ORF9-Luc strain. Ten well-tolerated, potent kinase inhibitors whose targets are critical mediators of VZV infection were identified. Receptor tyrosine kinases (EGFRK, NGFRK and PDGFRK) were pivotal for VZV replication and 3 potent compounds inhibited these targets (Tyrphostin AG1478, AG-879, Tyrphostin 9). Their common downstream substrates were also found to be necessary for VZV replication: protein kinase A (PKA, H-89•2HCl) and protein kinase C (PKC, GF 109203X and PKC-412). Other potent compounds blocked the activity of calmodulin-dependent protein kinase (CaMKII, KN-62) and glycogen synthase kinase 3-beta (GSK-3b, Indirubin-3’-monooxime and Kenpaullone). We also identified one compound with previously known antiviral activity, the cyclin-dependent kinase inhibitor Roscovitine. Thus VZV infection causes changes in the intracellular environment that expose antiviral targets in multiple pathways.

This abstract was presented at the 27th International Conference on Antiviral Research, May 12-16, 2014, Raleigh, NC.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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