WY-14643, a novel antiplatelet and antithrombotic agent targeting the GPIbα receptor
THROMBOSIS RESEARCH(2024)
Abstract
Background and purpose: Hypolipidemia and platelet activation play key roles in atherosclerotic diseases. Pirinixic acid (WY-14643) was originally developed as a lipid-lowering drug. Here we focused on its antiplatelet and antithrombotic abilities and the underlying mechanism. Experimental approach: The effects of WY-14643 on platelet aggregation was measured using a lumiaggregometer. Clot retraction and spreading on fibrinogen were also assayed. PPAR alpha(-/-) platelets were used to identify the target of WY-14643. The interaction between WY-14643 and glycoprotein Ib alpha (GPIb alpha) was detected using cellular thermal shift assay (CETSA), surface plasmon resonance (SPR) spectroscopy and molecular docking. GPIb alpha downstream signaling was examined by Western blot. The antithrombotic effect was investigated using mouse mesenteric arteriole thrombosis model. Mouse tail bleeding model was used to study its effect on bleeding side effects. Key results: WY-14643 concentration-dependently inhibits human washed platelet aggregation, clot retraction, and spreading. Significantly, WY-14643 inhibits thrombin-induced activation of human washed platelets with an IC50 of 7.026 mu M. The antiplatelet effect of WY-14643 is mainly dependent of GPIb alpha. CESTA, SPR and molecular docking results indicate that WY-14643 directly interacts with GPIb alpha and acts as a GPIb alpha antagonist. WY-14643 also inhibits phosphorylation of PLC gamma 2, Akt, p38, and Erk1/2 induced by thrombin. Noteworthily, 20 mg/kg oral administration of WY-14643 inhibits FeCl 3 -induced thrombosis of mesenteric arteries in mice similarly to clopidogrel without increasing bleeding. Conclusion and implications: WY-14643 is not only a PPAR alpha agonist with lipid-lowering effect, but also an antiplatelet agent as a GPIb alpha antagonist. It may have more significant therapeutic advantages than current antiplatelet agents for the treatment of atherosclerotic thrombosis, which have lipid-lowering effects without bleeding side effects.
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Key words
WY-14643,Antiplatelet,PPAR alpha,GPIb alpha,Antithrombotic
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