Thesis

Peptoids : targeting sequence specific high molecular weight materials for protein mimetic applications

Creator
Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2023
Thesis identifier
  • T16783
Person Identifier (Local)
  • 201881306
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • Synthetic biomaterials currently do not possess the molecular accuracy and dynamic biochemical activities found in natural biopolymers, such as proteins. For over fifty years, scientists have been working to bridge this gap by creating synthetic materials that mirror the intricate complexity and functionality of proteins. However, the challenge of devising improved design strategies and synthetic methods to create materials that encapsulate the full spectrum of folded, protein-like architecture using entirely non-natural building blocks remains. Poly N-substituted Glycine ‘Peptoids’ are an interesting class of peptide mimetics which have been demonstrating their ability as potential candidates which fulfil the objective of biomimicry. They provide bioinspired, yet non-natural, affordable, and stable chemical structures that overcome many issues associated with peptides. Their N-substituted Glycine backbones provide protease resistance while effectively mimicking the spacing between the essential chemical functions of bioactive peptides. Peptoids have been gaining significant attention due to their modular synthesis which allows precision sequence control and have recently been shown to possess simplified intermolecular interactions and unique self-assembled nanostructures that resemble proteins. In this thesis I present the study of two different peptoid systems which were used to develop functional high molecular weight materials to target protein mimicry. Our first approach focused on the use of surface functionalised peptoid nanosheets (PNS). These materials represent an interesting class of self-assembling nanostructures which have a thickness of about three nanometres and a length of up to 100 micrometres. As a result, they possess a large surface area which can be used as a structural scaffold. Through sidechain modification of PNS forming sequences, PNS with a variable density of surface accessible azide functional groups were prepared. Subsequent copper-catalysed azide–alkyne cycloadditions (CuAAC) allowed the attachment of complex species such as fluorophores, gold nanoparticles and cyclic (RGD) ligands to prepare functional PNS which were used in applications ranging from Cryo-electron microscopy to cell culture experiments with mesenchymal stem cells. In addition to PNS studies a novel synthetic approach which targets sequence specific high molecular weight poly-peptoids, using N-substituted glycine N-thiocarboxyanhydride (NNTAs) in combination with conventional solid phase peptoid synthesis (SPPS) was investigated. This is the first time ‘designed’ peptoid-block-polypeptoid species have been synthesised in this way, at the time of preparation. This method was developed in response to the requirements of attaining high molecular weight sequence specific peptide mimetics which could encompass the structure of natural proteins and peptides. Over the course of these studies, di-, tri- and branched co-polypeptoid possess low dispersity (Ð) were demonstrated. Subsequent polymerisation improvements are also provided which highlight solvent selection, resin consideration and how nitrogen bubbling impacts polymerisation. The combination of the aforementioned consideration culminates in the preparation of a A-B-A type tri-block antimicrobial species.
Advisor / supervisor
  • Lau, King Hang Aaron
Resource Type
Note
  • This thesis is restricted to Strathclyde users only until 30th November 2028.
DOI

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