Towards synthetic phage libraries

Abstract

A phage is essentially made up of a single-strand of DNA and a protein coat, which displays multivalently a peptide that is encoded for by the single strand of DNA.  The first part of this thesis describes the synthesis and screening of multivalent peptide dendrimer conjugates in order to discover if “peptide dendrimer conjugates could be utilised, as a possible way to increase the affinity of the weak binding peptide ligands to their integrin receptors.  In the same way that this had been achieved with multivalent carbohydrate ligands?”   This question was addressed in chapters 2 and 3.

Chapter 2 describes the solid-phase synthesis of dendrimers for the preparation of multivalent ligand scaffolds.  Chapter 3 describes the synthesis of multivalent peptide-dendrimer conjugates and their subsequent screening in an ELISA.  A multivalent competitive binding molecule for the α₄β₁ integrin was found which was 12-fold more potent than its monovalent form.

In the second part of the thesis the aim was to synthesise a synthetic phage, comprising of a peptide sequence displayed on a multivalent scaffold coupled to an oligonucleotide sequence (upon which PCR could be performed), encoding the peptide sequence.  Chapter 4 describes the synthesis of a scaffold, which could facilitate the synthesis of multivalent ligand libraries (synthetic phage libraries).  The synthesis and screening of unsymmetrical peptide-dendrimer conjugates on this scaffold are also described. Chapter 5 describes the development of a synthetic phage as well as the screening methodology used to detect the binding of a synthetic phage to an integrin receptor.

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