Wynne, Conor (2024) Responsive Synthetic Peptide Conjugates – From Sensors to Peptidomimetics. PhD thesis, National University of Ireland Maynooth.

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Abstract

The importance of luminescent peptide sensors and peptidomimetics lies in their ability to address challenges in detection, imaging, drug development, and various other fields. More specifically, luminescent peptide-conjugates are often biocompatible and can detect analytes at trace-levels. This makes them effective tools for the visualisation of cellular processes and molecular interactions, while aiding in early diagnosis and monitoring disease progression. Indeed, peptidomimetics are designed to mimic the biological activity of peptides while often offering enhanced stability and bioavailability, overcoming some of the many limitations associated with native peptides. This thesis will focus on the use of modified synthetic peptide-conjugates as potential luminescent sensors for the visualisation of Caspase-3, and the design of a completely new peptidomimetic-scaffold based on Squaratides – a hybrid mix of squaramides and peptides. The thesis opens with a literature review (Chapter 1) documenting the therapeutic history of peptides and the inherent functionalities that facilitate their diverse chemistries, all the way up to the luminescent applications of peptide-conjugates for selective sensing/visualisation of specific disease-related enzymes. Chapter 2 details the design, synthesis, and characterisation of a ratiometric fluorescent caspase-3 probe. This novel peptide-conjugate was investigated as a potential probe for the visualisation of caspase-3 via UV-vis/Fluorescence studies, enzyme kinetic(s) experiments, and selectivity studies. The probe was shown to be highly selective towards caspase-3, with kinetic data comparable to others reported in literature, while benefiting from the advantages of ratiometric detection. The design of a potential red-emitting naphthalimide-peptide probe for caspase-3 visualisation is also discussed. Chapter 3 aims to build on the idea of fluorescent visualisation using traditional organic fluorophores, but instead employs lanthanide luminescence, with their prolonged luminescence lifetimes and tuneable emission colours. This chapter reports the synthesis and characterisation of a family of novel, water-soluble squaramide-based cyclen ligands with varying symmetry and substitution patterns, including one ligand that may have the potential to act as a lanthanide-based caspase-3 probe. The photophysical properties of each squaramide antenna was investigated, with preliminary metal-centred luminescence emission spectra being obtained for Eu3+ and Tb3+ complexes. The final section (Chapter 4) documents the attempted synthesis of a novel class of peptidomimetics featuring a squaramide motif. The aim was to investigate the use of squaramides as potential peptidomimetics, by generating synthetic analogues of a previous pharmaceutical drug – Cilengitide – with the hope of improving its overall stability. This chapter outlines a versatile synthetic methodology for the production of Nβ-Fmoc alkyl-amines (from their respective commercially available amino acids) and their incorporation into cyclic Squaratide peptidomimetics.

Item Type:	Thesis (PhD)
Keywords:	Responsive; Synthetic; Peptide; Conjugates; Sensors; Peptidomimetics;
Academic Unit:	Faculty of Science and Engineering > Chemistry
Item ID:	18885
Depositing User:	IR eTheses
Date Deposited:	13 Sep 2024 14:25
URI:
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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