Nucleic acid templated synthesis of peptide bonds

Nuñez I Pertiñez, Samuel ORCID: 0000-0002-6804-1592 (2020). Nucleic acid templated synthesis of peptide bonds. University of Birmingham. Ph.D.

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Abstract

The conventional synthesis of peptides, by reactions performed under highly concentrated conditions or on solid phase, have been widely utilised to produce a variety of oligomers. This has facilitated the discovery of bioactive compounds and the mechanistic study of their function. Recently, nanotechnology has facilitated the synthesis of peptide bonds by directing the interactions between reactive groups, in order to produce the desired peptides. This thesis focuses on the use of nucleic acid templated synthesis (NATS) of peptide bonds, and on overcoming the hydrolysis of activated ester-labelled nucleic acids in aqueous solutions.

Chapter 1 gives a general overview of peptide bond formation strategies, highlighting nanotechnological approaches. The current scope and limitations of nucleic acid templated synthesis are also discussed. Chapter 2 is focused on the use of deep eutectic solvents (DESs) to minimise hydrolysis of activated esters, for the DNA templated synthesis (DTS) of peptide bonds. Chapter 3 describes the use of highly stable phenol ester-conjugated DNA adapters in aqueous buffered solution, and their in-situ activation towards aminolysis through oxo-ester mediated native chemical ligation (NCL). Chapter 4 explores if an alternative peptide nucleic acid (PNA) template could form stable duplexes in organic solvent, and thus, potentially template peptide bond synthesis reactions. Selective labelling of oligonucleotides has been a fundamental procedure in this thesis; in Appendix 2, the conjugation of fluorescent dibromomaleimide and dichloromaleimide to DNA has been explored; in addition, reductive amination has been explored as a chemistry for the modification of amine-labelled DNA with phenol esters.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):