Snake venom peptides: Potential therapeutic agents in thrombotic diseases

Abstract

The snake venoms are constituted of a true biochemical arsenal, consisting of several proteins and peptides with activities that have aroused the curiosity of researchers for centuries, in an attempt to understand its systemic action in order to get pharmacological applications. A number of snake venom proteins that interfere on platelet aggregation have been isolated from these venoms. However, there are no reports in the literature of small peptides interfering in aggregation. In the present work, we identify and characterize, for the first time, a heptapeptide (BaltPAi: platelet aggregation inhibitor from B. alternatus snake venom) and a decapeptide (BmooPAF: platelet-activating factor from B. moojeni snake venom), which potentially inhibits and induces the platelet aggregation, respectively. BmooPAi shows a rather specific inhibitory effect on collagen-induced platelet aggregation in human platelet-rich plasma, whereas it has little or no effect on platelet aggregation induced by adenosine diphosphate. The results presented here suggest that the BaltPAi consists of an amino acid sequence present in the C-terminal region of snake venom phospholipase A2 enzymes. This sequence would be responsible for the inhibition of platelet aggregation as well as for the cytotoxicity effects of tumor cells caused by these enzymes. Assays with monoclonal antibodies (anti-integrin α2b and anti-GP1BA) show a significant inhibitory effect on BmooPAF-induced platelet aggregation. On the other hand, anti-GPVI antibody shows no effect on platelet function. These findings, associated with molecular docking, indicate that BmooPAF induces platelet aggregation via binding to the GPIbα platelet receptor leading to αIIbβ3 integrin activation. These toxins could be of medical interest as tools for the development of novel therapeutic agents for the prevention and treatment of thrombotic disorders. The snake venoms are constituted of a true biochemical arsenal, consisting of several proteins and peptides with activities that have aroused the curiosity of researchers for centuries, in an attempt to understand its systemic action in order to get pharmacological applications. A number of snake venom proteins that interfere on platelet aggregation have been isolated from these venoms. However, there are no reports in the literature of small peptides interfering in aggregation. In the present work, we identify and characterize, for the first time, a heptapeptide (BaltPAi: platelet aggregation inhibitor from B. alternatus snake venom) and a decapeptide (BmooPAF: platelet-activating factor from B. moojeni snake venom), which potentially inhibits and induces the platelet aggregation, respectively. BmooPAi shows a rather specific inhibitory effect on collagen-induced platelet aggregation in human platelet-rich plasma, whereas it has little or no effect on platelet aggregation induced by adenosine diphosphate. The results presented here suggest that the BaltPAi consists of an amino acid sequence present in the C-terminal region of snake venom phospholipase A2 enzymes. This sequence would be responsible for the inhibition of platelet aggregation as well as for the cytotoxicity effects of tumour cells caused by these enzymes. Assays with monoclonal antibodies (anti-integrin α2b and anti-GP1BA) show a significant inhibitory effect on BmooPAF-induced platelet aggregation. On the other hand, anti-GPVI antibody shows no effect on platelet function. These findings, associated with molecular docking, indicate that BmooPAF induces platelet aggregation via binding to the GPIbα platelet receptor leading to αIIbβ3 integrin activation. These toxins could be of medical interest as tools for the development of novel therapeutic agents for the prevention and treatment of thrombotic disorders.