Novel cyclopropane-based β-turn mimetics: evaluation within simple and complex peptide systems

Neckebroeck, Albane (2019) Novel cyclopropane-based β-turn mimetics: evaluation within simple and complex peptide systems. PhD thesis, University of Glasgow.

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Abstract

Peptides are crucial in biological processes: depending on their structure and location in the body they play different important roles. In vivo, peptides can be cleaved by proteases that degrade and reduce their activity. Studies have shown that peptide bonds can be mimicked in order to prevent cleavage in vivo while retaining bioactivity and increasing the solubility as well as the ability to control the folding of the peptide. Furthermore, synthetic targets that mimic conformational features of biologically active protein’ domains have raised an intense interest for organic and medicinal chemists. The target in peptidomimetics nowadays is to get a better biological activity than natural occurring peptides by mimicking their structure.
This project focuses on the synthesis of peptidomimetics containing a cyclopropane as an amide bond isostere. Incorporation of a cyclopropane allows the molecule to be constrained conformationally, bringing hydrogen bond donor and acceptor groups together and facilitating reverse turn formation. To demonstrate this concept, the racemic and enantioenriched {GlyΔGly} dipeptide replacement units were synthesised and then incorporated at the centre of different short peptide chains. Optimisation and development of a new strategy is described in this thesis along with spectroscopic analyses to identify the secondary structure adopted by the peptides.
IR, concentration-dependant NMR, 2D NOESY NMR and circular dichroism (CD) analyses were conducted to prove the formation of this secondary structure. The studies were performed on peptides with different lengths, in order to demonstrate the propensity of bêta-turn formation depending on number of residues (from two to five) but also depending on the solvent. Intramolecular hydrogen bond formation was determined by NMR and IR spectroscopy, which allowed identification of the conformation. 2D NMR and CD spectroscopy allowed to isolate precisely the conformation adopted by the mimics.

Promising results from these model systems were obtained and applied to the synthesis of novel cyclopropane-based Leu-enkephalin and TrpZip peptide analogues. Those peptides are known to form bêta-turn and bêta-hairpin respectively, so controlling hydrogen bonding and the folding properties is particularly important.

Herein is described the synthesis of the longer analogues using the Gly-Gly surrogate designed and their full conformational analysis. CD and 2D NMR conformational analysis were conducted in order to identify the folding pattern of the analogues designed.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: peptides, synthesis, beta-turn, beta-hairpin, cyclopropane, TrpZip, Leu-enkephalin, peptidomimetic, turn mimic, NMR, CD, IR.
Subjects: Q Science > QD Chemistry
Colleges/Schools: College of Science and Engineering > School of Chemistry
Supervisor's Name: Clark, Professor Stephen
Date of Award: 2019
Depositing User: Miss Albane Neckebroeck
Unique ID: glathesis:2019-77882
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 13 Jan 2020 15:47
Last Modified: 05 Mar 2020 21:38
Thesis DOI: 10.5525/gla.thesis.77882
URI: http://theses.gla.ac.uk/id/eprint/77882

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