Thesis
Development of new chemical tools as crop protecting agents
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2022
- Thesis identifier
- T16191
- Person Identifier (Local)
- 201753456
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Due to factors such as an increasing population, climate change and resistance, there is a significant demand for novel, high quality lead compounds as crop protecting agents with novel modes of action (MoA). A desirable insecticidal target family are the Cys-loop receptors, a group of pentameric ligand-gated ion channels (pLGICs) which are activated by various neurotransmitters. Chapter 1 focused on the design, synthesis and structure-activity relationship (SAR) exploration of novel compounds targeting the insect γ-aminobutyric acid (GABA) receptor. Initial attempts focused on the synthesis of tricyclic sulfonamides, based upon a published lead compound allosterically modulating the human glycine receptor (GlyR), before moving to more conformationally flexible structures. Through biological evaluation of these compounds, the size and functionality of structures accommodated in the allosteric site were established. From these results, the original tricyclic sulfonamide structures show the most promise for biological activity. Chapter 2 focused on the design and synthesis of peptidic epitopes as protein-protein interaction (PPI) inhibitors of the nicotinic acetylcholine receptor (nAChR). To the best of our knowledge, there are no known modulators targeting the formation of the nAChR, which is assembled through the association of subunits. Using solid phase peptide synthesis techniques, wild type sequences mimicking the Nterminus of nAChR subunits were successfully generated. Following from the synthesis of the relevant unnatural alkenyl amino acid, four stapled peptides from each sequence were designed and synthesised as well as a scrambled sequence as a negative control. A total of nine peptides were tested in both in vitro and in vivo assays by our collaborators to determine the activity of these sequences towards the formation of nAChRs. Sequences based on nAChR regulator (NACHO), a chaperone protein which plays a key role in the assembly and expression of nAChRs, were also synthesised in an additional attempt to inhibit receptor formation. It is hoped that these PPI inhibitors will prevent the chaperone protein from recruiting nAChR subunits and therefore limit the formation of the receptor, presenting a new MoA in insecticide discovery.
- Advisor / supervisor
- Jamieson, Craig
- Rendine, Stefano
- Resource Type
- Note
- Previously held under moratorium from 7th April 2022 until 8th April 2024.
- DOI
- Embargo Note
Las relaciones
Elementos
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File | 2022-04-12 | Embargo |