A new Peptide Nucleic Acid (PNA) structure with potential for high affinity duplex and triplex binding

Kamperi, Victoria (2022) A new Peptide Nucleic Acid (PNA) structure with potential for high affinity duplex and triplex binding. Masters thesis, University of East Anglia.

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Abstract

Peptide Nucleic Acids (PNA) are synthetic DNA analogues, first discovered by Prof Peter E. Nielsen and his team in 1991. The deoxyribose phosphate backbone of DNA is replaced by a 2-aminoethyl glycine unit to which the nucleobases are linked through a methyl carbonyl linker. The lack of charge in the PNA’s backbone, allows for the formation of PNA-DNA or PNA-RNA chimeras with significantly higher affinity and selectivity than the relevant homo- or heteroduplexes. This tight binding of the DNA mimics to DNA or RNA, allows them to inhibit processes such as transcription and translation, leading to their potential as antisense or antigene agents.

Certain limitations with the initially suggested structure by Nielsen led to further investigations into synthesizing partially altered PNA structures that could overcome them, including PNAs forming triplex structures with double-stranded DNA. Topham et al. recently disclosed a theoretical modified PNA monomeric residue unit comprised of a 2-cis olefin carbonyl side-chain linker that is optimised to target thymine or uracil. Homopyrimidine PNAs have the ability to strand invade double-stranded homopurine DNA, leading to the formation of highly stable PNA∙DNA-PNA triple helix structures via Watson-Crick and Hoogsteen base pairing.

In this project, we investigated the synthesis of the PNA analogue described by Topham et al. Most of the initial synthetic pathway was successfully completed. However, a number of different directions had to be explored, due to complications with the synthesis of certain intermediate compounds, which are discussed and described in this report.

Item Type:	Thesis (Masters)
Faculty \ School:	Faculty of Science > School of Pharmacy
Depositing User:	Chris White
Date Deposited:	23 Mar 2023 15:54
Last Modified:	23 Mar 2023 15:54
URI:	https://ueaeprints.uea.ac.uk/id/eprint/91682
DOI:

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