Thesis defense Oliver Brun

Circulatory shocks are clinical emergencies with high associated mortality, partly imputable to inadequate clinical interventions. The understanding of their underlying pathophysiological mechanisms is therefore crucial to elaborate improved therapeutic strategies. Animal venoms are an abundant source of pharmacologically active compounds, including many peptides affecting the cardiovascular system. Such pharmacological tools can be employed to model cardiovascular disorders, thereby improving our understanding of their mechanisms and opening the way to new therapeutic approaches. This thesis focused more specifically on MT9, a peptide that displayed vasoactive properties in the course of preliminary studies.  We initially focused on the physiological characterization of  MT9’s effect on cardiac and vascular function, both      in and ex vivo in rats.In order to map the distribution of MT9’s receptors through optical imaging, we then developed a strategy to synthesize fluorescently labelled peptides. The process allowed for the production of a fluorescent analogue of MT9, which we attempted to use for transparized whole-heart imaging. This approach highlighted the need for covalent coupling of the peptide to its receptors. We therefore aimed at developing a photo-crosslinking strategy, which we first applied to the study of BeKm-1, an inhibitor of the potassium channel hERG.

This work highlights the yet-untapped potential of venom-derived peptides and their bioengineering as pharmacological tools for preclinical research and the development of novel therapeutic strategies.