The design and synthesis of peptide analogues targeting DNA four-way junctions

Ivens, Eleanor (2024) The design and synthesis of peptide analogues targeting DNA four-way junctions. Doctoral thesis, University of East Anglia.

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Abstract

Deoxyribonucleic acid (DNA) most commonly exists in vivo in its double-stranded helical form, with this being the primary target of DNA-targeting drugs. However, the substantial size of mega base DNA, and its high level of flexibility, means that it can also form other three-dimensional shapes, known as higher-order DNA. Many of these structures have been linked to diseases and are increasingly being explored as novel therapeutic targets.

The DNA four-way junction (4WJ) is a higher order DNA structure that is formed by the crossing over of DNA strands belonging to two separate dsDNA segments. In low salt environments, the 4WJ exists in the open conformation, whereas in high salt environments, the X-stacked conformation is adopted. The 4WJ is an important intermediate in DNA pressing and repair, such as during homologous recombination and site-specific recombination. These pathways are often relied upon by both bacterial and cancer cells.

Peptides have previously been discovered that bind to the 4WJ in its open conformation and have antibacterial effects. In this thesis, a series of novel biological assays were developed, to further access the 4WJ activity, double-stranded DNA activity and cancer cell cytotoxicity of these peptides. A combination of solid-phase peptide synthesis and multi-step organic synthesis were then used to produce novel peptide analogues, including cyclic peptides and linear peptides containing non-canonical amino acids. These molecules were predominantly shown to have similar biological results to the original peptides, including their ability to maintain 4WJ activity.

The rational design of 4WJ-targeting peptides was also investigated, based on protein/4WJ crystal structures. Although the two peptides designed, synthesised and tested were shown to have no 4WJ activity, this approach could be worth a further look, as more structural information on the DNA 4WJ is obtained.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Science > School of Chemistry, Pharmacy and Pharmacology
Depositing User:	Kitty Laine
Date Deposited:	04 Nov 2025 14:17
Last Modified:	04 Nov 2025 14:17
URI:	https://ueaeprints.uea.ac.uk/id/eprint/100898
DOI:

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