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Novel Conjugates of Porphyrins and Peptides as Light-Responsive Molecules and Materials

Dognini, P (2024) Novel Conjugates of Porphyrins and Peptides as Light-Responsive Molecules and Materials. Doctoral thesis, Liverpool John Moores University.

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The conjugation of biological molecules with functional small molecules is a common strategy in medicinal and biological chemistry to obtain compounds with improved properties and additional functionalities.In this work, the conjugation of peptides and porphyrins was studied. The thiol-fluoride Nucleophilic Aromatic Substitution (SNAr) was selected as conjugation tool because cysteine can be naturally present or easily introduced in peptide sequences, whilst meso- derivatised porphyrins with polyfluorinated rings are synthetically accessible. Initially, in Chapter 2, the reaction was optimised using N-acetyl cysteine and hexafluorobenzene as a model scaffold. Different reaction conditions were also explored on model peptides, and their compatibility with the starting reagents was tested. Two new base/solvent combinations for peptide stapling on hexafluorobenzene were identified and one of these proved to be a robust bioconjugation tool for peptides and porphyrins as well. Subsequently, in Chapter 3, bolaamphiphilic peptides with self-assembling behaviour were designed to include a cysteine and allow porphyrin coupling. When combined, porphyrin and self-assembling peptides can give origin to supramolecular systems with regular morphology and ordered arrangement that enhance the photochemical properties of embedded chromophores. The bola-porphyrin conjugates formed supramolecular structures under different conditions of concentration, pH, temperature, ionic strength, and time. Finally, in Chapter 4, it was observed that fully unprotected peptides containing two or more cysteines can cyclise by reacting twice or further with the same porphyrin. Besides the advantages of constrained peptides over their linear counterparts, the integration of a functional scaffold within the cyclic architecture is a step forward for the development of novel multifunctional molecules. This technique provided controlled access to cyclic, bicyclic, and tricyclic peptide systems that could be used as mimics of natural machineries, molecular probes, light-activated drugs, and biomarker detection tools. In conclusion, mastery of a novel bioconjugation strategy for peptides and porphyrins was demonstrated. The reaction occurs in solution with unprotected peptides and using peptide-compatible conditions, but can also be performed on-resin under specific circumstances. This indicates chemoselectivity, robustness and wide applicability. Exploiting this synthetic approach, light-responsive soft materials were obtained from the self-assembly of porphyrin and bolaamphiphilic peptides and polyfluorinated were introduced porphyrin as a versatile scaffold for the cyclisation of bioactive peptides.

Item Type: Thesis (Doctoral)
Uncontrolled Keywords: peptide; porphyrin; bio conjugation; Nucleophilic Aromatic Substitution; thiol; cysteine; fluorine; peptide stapling; peptide multicyclization; porphyrin strapping; self-assembly
Subjects: R Medicine > RS Pharmacy and materia medica
Divisions: Pharmacy & Biomolecular Sciences
SWORD Depositor: A Symplectic
Date Deposited: 31 Jan 2024 09:24
Last Modified: 09 Feb 2024 10:44
DOI or ID number: 10.24377/LJMU.t.00022464
Supervisors: Giuntini, F, Coxon, C and Darren, S
URI: https://researchonline.ljmu.ac.uk/id/eprint/22464
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