Due to factors such as an increasing population, climate change and resistance, thereis a significant demand for novel, high quality lead compounds as crop protectingagents with novel modes of action (MoA). A desirable insecticidal target family arethe 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, basedupon 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 ofstructures accommodated in the allosteric site were established. From these results, theoriginal tricyclic sulfonamide structures show the most promise for biological activity.Chapter 2 focused on the design and synthesis of peptidic epitopes as protein-proteininteraction (PPI) inhibitors of the nicotinic acetylcholine receptor (nAChR). To thebest of our knowledge, there are no known modulators targeting the formation of thenAChR, 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 thesynthesis of the relevant unnatural alkenyl amino acid, four stapled peptides from eachsequence were designed and synthesised as well as a scrambled sequence as a negativecontrol. A total of nine peptides were tested in both in vitro and in vivo assays by ourcollaborators to determine the activity of these sequences towards the formation ofnAChRs.Sequences based on nAChR regulator (NACHO), a chaperone protein which plays akey role in the assembly and expression of nAChRs, were also synthesised in anadditional attempt to inhibit receptor formation. It is hoped that these PPI inhibitorswill prevent the chaperone protein from recruiting nAChR subunits and therefore limitthe formation of the receptor, presenting a new MoA in insecticide discovery.
| Date of Award | 24 Mar 2022 |
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| Original language | English |
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| Awarding Institution | - University Of Strathclyde
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| Sponsors | University of Strathclyde |
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| Supervisor | Craig Jamieson (Supervisor) & Glenn Burley (Supervisor) |
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