Date of Award

10-4-2023

Publication Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry and Biochemistry

Keywords

disulfide;peptide;polymer;pseudopeptide;self-immolative polymer;stimuli-responsive

Supervisor

John Trant

Rights

info:eu-repo/semantics/embargoedAccess

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

Abstract

Biodegradable self-immolative polymers (SIPs), which degrade in response to a specific stimulus through an end-to-end depolymerization mechanism, introduce new levels of control for polymer science and have emerged as promising materials for a wide range of potential applications from biomedical devices, sensors, tissue engineering scaffolds, and drug delivery vehicles to more environmentally friendly substitutes for traditional plastics. First generation SIPs effectively degrade, but the byproducts include p-quinone methides, excellent alkylators, that are potentially toxic to humans and the environment and limited their potential application for biomedicine. Second generation systems resolve this issue by using less toxic materials, but truly biocompatible systems would be preferable. The first portion of this thesis reports progress towards third generation SIP systems that use a linear biodegradable, non toxic and potentially amphiphilic backbone, derived from amino acid building blocks. The potential for differential functionalization makes the resulting SIPs useful as biocompatible traceless drug-delivery capsules and as the basis for biomedical device development and as functional switches for 3-dimensional bioprinting applications. The main areas of investigation in this thesis include the synthesis of monomer and polymer backbone, the study of polymer degradation, toxicity, and computational study of this system. The following section of the thesis discusses the significance of disulfide bond formation in the organization of proteins and peptides, particularly in determining their ternary structure. Formation of the correct disulfide bonds between the correct cysteine residues facilitates the formation of the correct three-dimensional structure, especially in peptides. Disulfide bonds however present challenges in synthesizing peptides and proteins using production biotransformation systems; while the linear sequence may be readily programmed into DNA, the information regarding which disulfide bonds should be formed is often regulated by additional factors and is part of the post-translational modification and the incorrect bonds may be formed should the peptide be made in a cell line not originating from the natural host. This issue can be addressed chemically by ensuring that each pair of cysteine residues involved in a disulfide bond have different protecting groups compared to the other pairs. By sequentially removing these protecting groups from different cysteine pairs, one can achieve selective disulfide bond formation. Nevertheless, this approach requires meticulous chemical planning and execution, demanding significant expertise and facing potential challenges, which is also a key focus of this thesis. The aim is to develop protecting groups that allow highly selective formation of multiple disulfide bonds during peptide synthesis, without the need for additional reagents. Simply increasing the temperature after synthesis can generate the disulfide bonds. This technology could simplify the process, making disulfide-containing peptides more accessible to peptide chemists, even those without extensive experience in the field.

Available for download on Tuesday, February 11, 2025

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