Abstract
Chronic pain is a debilitating neurological disease that affects 20% of the world’s population. Compelling evidence has implicated voltage-gated sodium (NaV) channels in pain perception, particularly those found in peripheral sensory neurons. Therefore, several NaV channel subtypes, including NaV1.1, 1.3, 1.6, 1.7, 1.8 and 1.9, represent attractive targets for analgesic development. Toxins from venomous creatures provide a rich source of NaV channel modulators with high potency and affinity for their targets. These characteristics, together with intrinsic stability afforded by complex disulfide networks, make toxins suitable leads for drug development. Many NaV channel toxin inhibitors have been well studied, for example, μ- conotoxins from cone snails, while others, such as HSTX-I from leeches, have only recently emerged. This thesis aims to characterise animal-derived peptide inhibitors of NaV channels and validate their potential as viable drug leads for neurological diseases, such as chronic pain.Chapter 1 comprises an introduction and literature review, with the first half providing an overview of NaV channels, venom-derived toxin modulators and peptide drug development. The second half of the chapter covers specific animal toxins used in this thesis and incorporates a literature review on the current status of NaV channels and μ-conotoxins. Chapters 2 and 3 explore the pharmacological and structural characterisation of novel NaV channel inhibitors HSTX-I and SxIIIC. Chapter 4 evaluates the structure-activity relationship of μ-conotoxins and NaV channels and aims to identify key residues which influence potency and subtype selectivity. Chapter 5 summarises the main conclusions of this thesis and provides an overview of the outstanding research questions arising from this work.
Published Version
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