A Novel Direct Factor Xa Inhibitory Peptide with Anti-Platelet Aggregation Activity from Agkistrodon acutus Venom Hydrolysates

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.

The pyrrolidinoindoline alkaloid Psm2 inhibits platelet aggregation and thrombus formation by affecting PI3K/Akt signaling

“…In an arterio-venous shunt model, developing thrombi contain aggregated platelets that adhere to the thrombogenic silk thread and fibrin [1] . Thus, arterial thrombus formation models have been considered classical assays for determining the antithrombotic activities of an antiplatelet "drug".…”

“…Thrombosis plays a crucial role in the development of some cardiovascular disorders, including acute coronary syndrome, myocardial infarction and pulmonary embolism [1] . In the process of thrombus formation, platelets adhere to the vascular wall, become activated, release agonists and finally aggregate at the injured vascular site [2,3] .…”

A tryptophan derivative TD-26 attenuates thrombus formation by inhibiting both PI3K/Akt signaling and binding of fibrinogen to integrin αIIbβ3

“…To estimate thrombus formation, a previously described method [23,24] was used. SD rats were randomly divided into 5 groups with 6 rats (males and females in half) in each group and injected intravenously with TD-26 (0.3, 1, 3 mg/kg), aspirin (50 mg/kg) or vehicle.…”

Bioactive peptides and proteins as alternative antiplatelet drugs

“…Factor Xa is a key component of the prothrombinase complex that converts prothrombin to thrombin. ACH‐11 inhibits the catalytic function of Factor Xa and platelet aggregation, without serious bleeding risk …”

“…Therefore, particular attention needs to be attributed to these parameters in the preparation of peptides . Numerous recent studies have illuminated that peptides exhibit antithrombosis and antiplatelet aggregation activities . This review summarizes the potential of peptides from natural sources, to exhibit antiplatelet aggregation activity.…”