Introduction and general objectives - Animal venoms and secretions are sources of novel pharmacologically active molecules of potential therapeutic value. We have screened venoms aiming to discover, identify and isolate peptide molecules active in the mammalian haemostatic system. This research initiative yielded a portfolio of promising drug candidates comprising Lopap and Losac from bristles of the Lonomia obliqua caterpillar, Amblyomin-X from saliva of the Amblyomma cajennense tick, and a LAPP-like inhibitor from the Haementeria depressa leech. These novel recombinant proteins and synthetic peptides turned out to be multifunctional molecules, which are presently under different phases of development processes. However, their molecular mechanisms of action remain unknown. The main objective of this project is to elucidate the mechanisms by which these peptide toxins interfere with complex cellular processes such as survival, death and tissue regeneration, through theoretical and experimental models.
Specific objectives – a) Amblyomin-X is a potential candidate to treat cancer and metastasis. It is a coagulation inhibitor, which likely acts through the factor VIIa/tissue factor (FVIIa/TF) biochemical pathway . Tumor metastasis has been linked to the aberrant expression of TF, which normally functions as a blood coagulation factor and can lead to the production of proangiogenesis factors as vascular endothelial growth factor (VEGF) . We aim at uncovering the molecular pathways involved in the Amblyomin-X anti-tumor activity; b) Lopap is a prothrombin activator which belongs to the lipocalin family and displays serine protease-like activity with procoagulant effect . It also induces cytokine secretion and antiapoptotic pathways in human cultured endothelial cells . A Lopap-derived peptide, which contains a lipocalin sequence signature  is capable of inducing collagen synthesis in fibroblast culture and in the animal dermis. The challenge here is to understand how a short Lopap-derived peptide can specifically interfere with major cellular signaling pathways; c) Losac is the first protein from the hemolin family exhibiting procoagulant activity through selective proteolysis of coagulation factor X just like the RVV-X isolated from the Daboia russelli snake venom . Losac also promotes survival of neurons and endothelial cells, suggesting that it can be of therapeutic value in the treatment of neurodegenerative diseases. The challenge is to work out the molecular mechanisms underlying Losac’s pro-survival activity; d) LAPP-like is a potent inhibitor of collagen-induced platelet aggregation which directly acts on the receptor GPIba. This receptor plays key roles in atheroma formation and inflammatory processes and has been intensely studied in metastasis models where platelets seem to be a crucial input increasing the severity of the disease. Thus, we will explore LAPP-like effects on in vivo and in vitro experimental models of metastasis and atherosclerosis.
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