Polysulfated Trehalose as a Novel Anticoagulant Agent with Dual Mode of Action

Abstract

Physiological hemostatic balance is a coordinated outcome of counteracting coagulation and fibrinolytic systems. An imbalance of procoagulant and anticoagulant factors may result in life threatening thromboembolism. Presently, anticoagulant administration is the first line of therapy for the treatment of these conditions and several anticoagulants have been approved, including various forms of heparin. However, the polyanionic nature and multispecificity of heparin pose several complications. Generally, the polysulfated compounds with antithrombotic potential are thought to have feasible synthetic procedures with much less bleeding, thus having favourable safety profiles. Here we report the synthesis of a novel compound, trehalose octasulfate and the assessment of its anticoagulation potential. Molecular docking of trehalose and trehalose octasulfate with antithrombin showed a specificity switch in binding affinity on sulfation, where trehalose octasulfate interacts with critical residues of AT that are either directly involved in heparin binding or in the conformational rearrangement of AT on heparin binding. An in vitro analysis of trehalose octasulfate demonstrated prolonged clotting time. Lead compound when intravenously injected in occlusion induced thrombotic rats showed remarkable reduction in the size and weight of the clot at a low dose. Delay in coagulation time was observed by analysing blood plasma isolated from rats preinjected with trehalose octasulfate. A decrease in Adenosine 5′-Diphosphate (ADP) induced platelet aggregation indicated a probable dual anticoagulant and antiplatelet mechanism of action. To summarize, this study presents trehalose octasulfate as a novel, effective, dual acting antithrombotic agent.

Heparin mimetics with anticoagulant activity

“…found that the commercially available sucrose octasulfate ( 18 ) directly inhibits thrombin with high potency but low efficacy after binding with exosite II of thrombin . Jairajpuri and co‐workers synthesized trehalose octasulfate ( 19 ) as a dual anticoagulant/antiplatelet agent but the mechanism of action was not fully elucidated …”

Protein disulfide isomerase uses thrombin–antithrombin complex as a template to bind its target protein and alter the blood coagulation rates

“…Activated partial thromboplastin time (APTT), prothrombin time (PT), and thromboplastin time (TT) clotting assays were performed by utilizing commercially available kits and in accordance with the manufacturer's instructions. All the experiments were performed by the previously described protocol [ 22 , 23 ]. Each test run was repeated three times with 175 nM of wtPDI and its variants were used during the clotting time experiments, where the protein was added exogenously.…”

Designing Smaller, Synthetic, Functional Mimetics of Sulfated Glycosaminoglycans as Allosteric Modulators of Coagulation Factors

“…109,110 Several natural products in their fully or partially sulfated forms have now been evaluated as anti-coagulants. These include sulfated quercetins, 111 sulfated trehalose, 112 and sulfated esculin. 113 Of these, the latter has been shown to be selective for AT over HCII and is sufficiently functional in reducing thrombus formation in the rat model of venous thrombosis.…”