Abstract
Animal venoms have evolved for defence and to facilitate predation. The toxins they contain are often intended to incapacitate the prey or predator, by targeting key physiological functions such as hemostasis, neuromuscular junction or pain perception and are generally peptides. These disulfide-rich venom peptides have a constrained three-dimensional structure and increased plasma stability compared to linear peptides. The conservation and similarity of prey/predator receptors to human receptors makes venom peptides a unique source of lead compounds for the design of pharmacological tools and therapeutic compounds. Although most typical toxins modulate ion channels that transmit nerve information, we first studied the potential of linear and 1-bridge toxins on more rarely explored targets such as G-protein coupled receptors (Chapter 1). However, since most toxins are composed of 2 or 3 disulfide bridges, we then opted to set up a robust strategy for synthesis of toxins with two disulfide bridges. Thus, the synthesis of several α-conotoxins (chapter 2) allowed their structural characterization by NMR and pharmacological characterizaton on nicotinic receptors. An extension of this work on a promising sequence with dual activity on muscle and neural receptors was performed by N-C cyclization. This work was extended to the synthesis of longer toxins targeting other ion channels and containing 3 disulfide bridges (chapter 3). Finally, the synthesis of new toxins discovered in databases from various venom gland transcriptomes was initiated, and we performed proteo-transcriptomic analysis of snake venom for the identification of new toxins (Chapter 4).