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Designing Natural Product Hybrids Bearing Triple Antiplatelet Profile and Evaluating Their Human Plasma Stability
Antonis Tsiailanis1, Maria Tsoumani2, Evgenios K Stylos1,3
1Section of Organic Chemistry and Biochemistry, Department of Chemistry, University of Ioannina, Ioannina, Greece.
Abstract:
Cardiovascular diseases (CVDs) are becoming major contributors to the burden of disease due to genetic and environmental factors. Despite current standard oral care, cardiovascular risk remains relatively high. A triple antiplatelet therapy with a cyclooxygenase-1 (COX-1) inhibitor, a P2Y12 receptor antagonist, and a protease-activated receptor-1 (PAR-1) antagonist has been established in the secondary prevention of atherothrombosis in patients with acute myocardial infraction and in those with peripheral artery disease. However, due to the combinatorial use of three different drugs, patients receiving this triple therapy are exposed to enhanced risk of bleeding. Conforming to polypharmacology principles, the discovery of a single compound that can simultaneously block the three platelet activation pathways (PAR-1, P2Y12, and COX-1) is of importance. Natural products have served as an inexhaustible source of bioactive compounds presenting a diverse pharmaceutical profile, including anti-inflammatory, antioxidant, anticancer, and antithrombotic activity. Indeed, principal component analysis indicated that natural products have the potential to inhibit the three aforementioned pathways, though existed reports refer to single inhibition mechanism on specific receptor(s) implicated in platelet activation. We thus set out to explore possibilities that take advantage of this potential of natural products and shape the basis to produce novel compounds that could simultaneously target PAR-1, P2Y12, and COX-1 platelet activation pathways. Polyunsaturated fatty acids (PUFAs) have multiple effects leading to improvements in blood pressure and cardiac function and arterial compliance. A promising approach to achieve the desirable goal is the bioconjugation of natural products with PUFAs. Herein, we describe the principles that should be followed to develop molecular hybrids bearing triple antiplatelet activity profile.
Insights
Developing novel compounds from natural products is key to creating a single drug that inhibits three platelet activation pathways: cyclooxygenase-1 (COX-1), P2Y12, and protease-activated receptor-1 (PAR-1). This approach aims to reduce bleeding risks associated with current triple antiplatelet therapies.
Area of Science:
- Pharmacology
- Natural Product Chemistry
- Cardiovascular Research
Background:
- Cardiovascular diseases (CVDs) pose a significant global health burden, with current treatments having limitations.
- Existing triple antiplatelet therapies (COX-1 inhibitor, P2Y12 antagonist, PAR-1 antagonist) reduce atherothrombosis risk but increase bleeding complications.
- A single agent targeting multiple platelet activation pathways is desirable for improved safety and efficacy.
Purpose of the Study:
- To explore the potential of natural products for developing novel compounds with simultaneous inhibition of COX-1, P2Y12, and PAR-1 pathways.
- To establish principles for creating molecular hybrids that combine natural product bioactivity with polyunsaturated fatty acids (PUFAs) for triple antiplatelet effects.
Main Methods:
- Leveraging the diverse bioactivity of natural products, known for anti-inflammatory, antioxidant, and antithrombotic properties.
- Investigating natural products' potential to inhibit key platelet activation receptors (PAR-1, P2Y12) and enzymes (COX-1).
- Proposing bioconjugation of natural products with PUFAs as a strategy to develop multi-targeted antiplatelet agents.
Main Results:
- Principal component analysis suggests natural products can inhibit the three targeted pathways.
- Existing research often focuses on single-target inhibition, highlighting the need for multi-target approaches.
- The study outlines principles for designing molecular hybrids with combined antiplatelet activities.
Conclusions:
- Natural products offer a promising source for developing single compounds targeting COX-1, P2Y12, and PAR-1 pathways.
- Bioconjugation with PUFAs presents a viable strategy for creating novel triple antiplatelet agents.
- This research lays the groundwork for innovative therapeutic strategies in cardiovascular disease prevention.
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