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Advisory Committee Chair

Peter E Prevelige

Advisory Committee Members

David M Bedwell

Trevor Douglas

Charles L Turnbough

Mark Walter

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Modification of virus capsids as target-specific delivery devices has become highly popularized in recent years and P22 bacteriophage has been proposed as a potential candidate for development of a targeting drug delivery system. As a proof of concept for our system, we hypothesized that the A-domain of P22 coat protein could be utilized to alter the binding affinity of virus-like procapsids for biological targets. Addition of acidic residues to the A-domain revealed that this could be accomplished through the quarternary localization of charged residues in three-dimensional space without interrogating procapsid assembly. Further manipulations implemented in vivo were performed to examine the biological role of this domain on assembly and maturation. These studies demonstrated that while the A-domain allows for assembly of procapsids, insertions to this region greater than two residues restrict the virus from forming the mature morphology and furthermore there is strong selection pressure to limit insertions in this region. This work demonstrates that the P22 capsid structure can be used to alter the specificity of the virus for alternative targets as well as the ability to engineer controllable stability of the capsid allowing for release of internal cargo.

maturationP22.mp4 (8513 kB)
Video - Maturation P22

Supplemental Figures.pdf (585 kB)
Supplemental Figures

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