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UBC Theses and Dissertations

Multivalent pIII phage display libraries : selected issues and applications Wilson, Daniel Ross


By the use of model Ff phage libraries displaying (i) variants of the Plasmodium falciparum circumsporozoite protein (CSP) immunodominant tetrapeptide repeats and (ii) peptides derived from the gene encoding Bordetella pertussis filamentous hemagglutinin (FHA), the application potential of phage display was illustrated and several issues related to the utility of phage display were examined. Studies with the P. falciparum model, together with a statistical analysis of conformations adopted by aspartate/asparagine-proline residue pairs in proteins deposited in the Brookhaven Protein Data bank, provided insight into the structure of the CSP repeats and into the epitopes recognized by a panel of anti-CSP monoclonal antibodies. These studies also served to demonstrate the technical simplicity and general utility of phage display when applied to simple models. The more complex model, involving phage display of B. pertussis FHA-derived peptides, served as a model for genomic libraries. Work with this model led to the identification of fourteen antigenic regions within the large (200 kDa) FHA protein; these findings were both confirmed by and greatly extend previous antigenic analyses of FHA. This model also demonstrated that while construction of genomic phage display libraries is technically achievable, limitations imposed by phage and host biology may limit their utility and broad applicability. Difficulties encountered while exploring this model indicate that vector design is important to library construction and employment, and that attempts to display some foreign peptides on the phage surface can so profoundly affect phage/host biology that in some cases incompatible peptides will be "corrected" so as to enable their display. These and other issues of phage/host biology and their impact on phage display are discussed, including the need for fundamental studies into the influence of the nature (composition and sequence) of a peptide on its ability to be incorporated into virions.

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