Section of Organic Chemistry and Biochemistry, Department of Chemistry, University of Ioannina, Ioannina 45110, Greece; Biotechnology Laboratory, Department of Biological Applications and Technology, University of Ioannina, Ioannina 45110, Greece.
Section of Organic Chemistry and Biochemistry, Department of Chemistry, University of Ioannina, Ioannina 45110, Greece.
Biochim Biophys Acta Gen Subj. 2017 Nov;1861(11 Pt A):2609-2618. doi: 10.1016/j.bbagen.2017.08.018. Epub 2017 Aug 24.
The current standard-of-care antiplatelet therapy in cardiovascular disease patients is consisted of cyclooxygenase-1 (COX-1) inhibitor aspirin, along with a platelet receptor P2Y antagonist. Recently, the triple antiplatelet therapy with aspirin, a P2Y receptor antagonist and a protease activated receptor-1 (PAR-1) antagonist, has been suggested for the secondary prevention of atherothrombotic events, however presented an increased risk of bleeding. Therefore, the quest for novel antiplatelet agents simultaneously targeting the three pathways with improved efficacy/safety profile is of immense importance. Flavonoids as pre-validated ligands for numerous targets could serve as scaffolds targeting the three platelet activation pathways.
Computational methods, Ultra High Performance Liquid Chromatography-Tandem Mass Spectrometry (UHPLC-MS/MS) plasma stability and in vitro platelet aggregation experiments were used to establish the antiplatelet activity of the flavonoid naringenin and its conjugates.
In silico studies indicated that naringenin could bear a potent triple antiplatelet activity by inhibiting different platelet aggregation mechanisms. However, we found that in human platelets naringenin has diminished activity. We rationally designed and synthesized different naringenin conjugates aiming to amplify the antiplatelet activity of the parent compound. UHPLC-MS/MS revealed a slow degradation rate for a docosahexaenoic acid (DHA) - naringenin conjugate in human plasma. The antiplatelet profile of the new analogues was evaluated against in vitro platelet aggregation induced by several platelet agonists.
The DHA - naringenin hybrid presented triple antiplatelet activity simultaneously targeting PAR-1, P2Y and COX-1 platelet activation pathways.
Natural products could offer a rich source for novel bioactives as a powerful alternative to the current combinatorial use of three different antiplatelet drugs.
目前心血管疾病患者的标准抗血小板治疗包括环氧化酶-1（COX-1）抑制剂阿司匹林，以及血小板受体 P2Y 拮抗剂。最近，阿司匹林、P2Y 受体拮抗剂和蛋白酶激活受体-1（PAR-1）拮抗剂的三联抗血小板治疗已被推荐用于动脉血栓事件的二级预防，但出血风险增加。因此，寻找同时针对三种途径、疗效/安全性改善的新型抗血小板药物至关重要。类黄酮作为多种靶点的预先验证配体，可作为靶向三种血小板激活途径的支架。
计算方法、超高效液相色谱-串联质谱（UHPLC-MS/MS）血浆稳定性和体外血小板聚集实验用于确定类黄酮柚皮素及其缀合物的抗血小板活性。
计算机研究表明，柚皮素通过抑制不同的血小板聚集机制，可能具有潜在的三重抗血小板作用。然而，我们发现柚皮素在人血小板中的活性降低。我们合理设计并合成了不同的柚皮素缀合物，旨在放大母体化合物的抗血小板活性。UHPLC-MS/MS 显示人血浆中二十二碳六烯酸（DHA）-柚皮素缀合物的降解速度较慢。新类似物的抗血小板谱通过几种血小板激动剂诱导的体外血小板聚集来评估。
DHA-柚皮素杂合体具有三重抗血小板活性，同时靶向 PAR-1、P2Y 和 COX-1 血小板激活途径。
天然产物为新型生物活性物质提供了丰富的来源，是目前三种不同抗血小板药物联合使用的有力替代方法。
