Abstract
Snake venom is a natural substance that contains numerous bioactive proteins and peptides, nearly all of which have been identified over the last several decades. In this study, we subjected snake venom to enzymatic hydrolysis to identify previously unreported bioactive peptides. The novel peptide ACH-11 with the sequence LTFPRIVFVLG was identified with both FXa inhibition and anti-platelet aggregation activities. ACH-11 inhibited the catalytic function of FXa towards its substrate S-2222 via a mixed model with a Ki value of 9.02 μM and inhibited platelet aggregation induced by ADP and U46619 in a dose-dependent manner. Furthermore, ACH-11 exhibited potent antithrombotic activity in vivo. It reduced paralysis and death in an acute pulmonary thrombosis model by 90% and attenuated thrombosis weight in an arterio-venous shunt thrombosis model by 57.91%, both at a dose of 3 mg/kg. Additionally, a tail cutting bleeding time assay revealed that ACH-11 did not prolong bleeding time in mice at a dose of 3 mg/kg. Together, our results reveal that ACH-11 is a novel antithrombotic peptide exhibiting both FXa inhibition and anti-platelet aggregation activities, with a low bleeding risk. We believe that it could be a candidate or lead compound for new antithrombotic drug development.
Highlights
Thrombosis is a leading cause of morbidity and mortality throughout the world and plays a pivotal role in the pathogenesis of numerous cardiovascular disorders, including acute coronary syndrome, myocardial infarction, unstable angina, deep-vein thrombosis and pulmonary embolism[1]
A number of bioactive peptides have been obtained by enzymatic methods, and those peptides include angiotensin-converting enzyme (ACE) inhibitory peptide from tuna frame protein hydrolysate[12], antioxidant peptide from grass carp muscle hydrolysate[13], antimicrobial peptide from anchovy hydrolysate[14], and anticoagulant peptide from scorpion protein and goby muscle protein hydrolysate[15,16]
Snake venoms have been a rich source of novel antithrombotic agents because they contain a variety of proteins and peptides that affect thrombosis and hemostasis[17,18,19,20]
Summary
Thrombosis is a leading cause of morbidity and mortality throughout the world and plays a pivotal role in the pathogenesis of numerous cardiovascular disorders, including acute coronary syndrome, myocardial infarction, unstable angina, deep-vein thrombosis and pulmonary embolism[1]. FXa, a trypsin-like serine protease, functions at the convergence of the extrinsic and intrinsic coagulation pathways It plays a central role in the coagulation cascade by catalyzing the production of thrombin, leading to further clot formation and wound closure[2]. The search for thrombin inhibitors has been the focus of early antithrombotic drug development efforts because thrombin plays multiple roles in normal coagulation, including catalyzing the cleavage of fibrinogen to fibrin, catalyzing the formation of FVa and FVIIIa, and activating platelets[3]. To the best of our knowledge, this is the first report of the enzymatic hydrolysis of snake venom and the discovery of a new peptide demonstrating dual inhibition of FXa and platelet aggregation
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