The inhibition of platelet aggregation is a key process in prevention of blood clotting that is implicated in venous thrombosis. Dietary polyunsaturated fatty acids have been shown to inhibit the process of platelet aggregation. However, their mechanism of action is poorly understood. The process of platelet aggregation proceeds through three major pathways- cyclooxygenase (COX)- CYP5A1 (thromboxane synthase) pathway, ADP induced and collagen-induced pathways. The COX-CYP5A1 pathway metabolizes arachidonic acid (AA) to thromboxane A<sub>2, </sub>a pro-aggregatory molecule. It is hypothesized that dietary fatty acids inhibit platelet aggregation through the COX-CYP5A1 pathway by inhibiting metabolism of AA by COX through competitive inhibition. In our studies, we examine the mechanism of dietary fatty acids on the COX-CYP5A1 pathway through a coupled activity enzyme assay by measuring product formation in the presence of these fatty acids. Additionally, we explore the derivatization of dietary fatty acids with pre-existing drug molecules towards the inhibition of platelet aggregation. The carboxylate moiety of the dietary fatty acids poses a challenge towards biological absorption due to their ionic nature at physiological pH. The conjugation of these with other inhibitors of platelet aggregation could be effective a pro-drug like species providing a dual source of inhibition. We further perform characterization of the hydrolytic properties of these molecules and mechanistic studies to investigate their pathway of inhibition.

Development of fatty acid derivatives to inhibit platelet aggregation and investigating their biochemical mechanism

251st National Meeting (2016)

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