Abstract
Integrin αIIbβ3 plays a pivotal role in platelet aggregation. Three αIIbβ3 antagonists have been approved by the Food and Drug Administration (FDA) for the treatment of cardiovascular diseases. Unfortunately, all of these three drugs can cause the side effect of severe bleeding. Therefore, developing a new αIIbβ3 antagonist with low bleeding was needed. In the present study, we screened compounds by using a fibrinogen/integrin αIIbβ3 enzyme-linked immunosorbent assay (ELISA), and a novel αIIbβ3 antagonist ANTP266 was attained. The antithrombotic effects of ANTP266 were estimated by using two animal models, the bleeding risk was estimated by using a mice tail cutting assay, and the plasma half-life time was tested by LC-MS/MS. The results showed that ANTP266 potently decreased thrombosis formation, while not prolonging bleeding time at its effective dosage. The bleeding of ANTP266 reduced rapidly as time went on from 5 to 60 min, but tirofiban produced high bleeding continuously. The plasma half-life of ANTP266 in rats was 10.8 min. Taken together, ANTP266 is an effective antithrombotic agent with a low bleeding risk. The shorter bleeding time benefits from its short plasma half-life. ANTP266 could be a candidate for developing the αIIbβ3 antagonist of rapid elimination for a patient undergoing percutaneous coronary intervention.
Highlights
Cardiovascular diseases (CVDs) are recognized as the leading causes of death in the world
We found that ANTP266 restrained platelet aggregation stimulated by various agonists via interacting with αIIbβ3
Platelets are in a “resting” state and activated when they come into contact with some adhesive proteins, such as collagen, as well as von Willebrand factor (VWF), and come into contact with platelet agonists, such as thrombin, ADP, and thromboxane A2
Summary
Cardiovascular diseases (CVDs) are recognized as the leading causes of death in the world. Pathological conditions can trigger platelet activation, lead to platelet aggregation, and incur cardiovascular disorders [3,4]. ΑIIbβ is a transmembrane glycoprotein, composed of αIIb and β3 subunit [5]. Integrin αIIbβ, which is the most abundant adhesion receptor on the surface of platelets with numbers as high as 60,000–80,000 per platelet, has been revealed to have a pivotal role in the process of platelet aggregation. It has two states: resting and active state. ΑIIbβ inhibitors can be used for antithrombosis therapy [7,8]
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