College of Science and Health Theses and Dissertations

Date of Award

Spring 6-8-2018

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Biology

First Advisor

Sarah Connolly, PhD

Second Advisor

Eric Norstrom, PhD

Third Advisor

Jason Bystriansky, PhD

Abstract

Fusion of the viral and host cell membranes during herpesvirus entry into cells is mediated by glycoprotein B (gB), a class III viral fusion protein that is essential and conserved in all herpesviruses. gB is believed to mediate fusion by inserting into a target cellular membrane and refolding from a prefusion to a postfusion conformation to bring the viral and cellular membranes together. Electron cryotomography revealed two distinct gB conformations and the postfusion gB crystal structure has been solved, however the crystal structure of the prefusion conformation and the details of how gB refolds to execute fusion remain uncertain. A previous mutagenesis study demonstrated that a region in herpes simplex virus (HSV) gB, termed the coil-arm region, contributes to fusion. This coil-arm region resembles the six-helix bundle that is predicted to provide energy to drive fusion in class I fusion proteins. A panel of small molecule compounds that were designed to inhibit interactions of the coil-arm region in HSV gB were screened. One compound significantly decreased HSV1 and HSV2 entry into cells with an IC50 in the low µM range. The compound was not cytotoxic and inhibited herpesvirus entry specifically. The compound inhibited entry at a step after virus binding and was able to inhibit fusion in a cell-cell fusion assay. Design of a potent fusion inhibitor could lead to drug candidates that target this conserved fusion protein and clarify how the protein functions, potentially providing a new tool to study the gB conformational change and provide a broader understanding of how similar class III viral fusion proteins refold.

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