Venoms-based drug discovery: bioassays, electrophysiology, high-throughput screens and target identincation
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The study of venoms is driven by a desire to understand the structural and functional diversity of venom components and, in particular, the mechanism of action of lethal components from medically important animals such as scorpions, spiders, stonefish and snakes. Initially, target-driven venom screens were rare. Bioassays in whole animals or isolated tissues were used to characterise behavioural and physiological parameters of venoms. Molecular fractionation of venom components required more specific bioassays to identify components based on pharmacological or physiological responses of anaesthetised whole animals or tissue preparations such as skeletal muscle, smooth muscle and isolated blood vessels. These assays can be extremely informative because they often measure an integrated tissue response that cannot be seen in more defined cellular assays. Despite this, the convenience and sensitivity of modern biochemical and cellular bioassays means that they are now widely used to characterise venom components. Such assays have the advantage that they can be miniaturised and performed in multiwell plates. Together with the development of high-throughput platforms such as the FLIPR and automated electrophysiology devices, these miniaturised assays have facilitated the high-throughput screening of venoms components against enzymes, receptors and ion channels, many of which are validated drug targets. These assay platforms are likely to be a major driver that will significantly expedite future venoms-based drug discovery efforts. The aim of this chapter is to summarise the various assays that are being used to identify and determine the mode of action of drug leads derived from animal venoms.