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Background <p>Hemostasis prevents excessive bleeding through clot formation; however, uncontrolled thrombin activity can lead to thrombosis-related conditions such as deep vein thrombosis and myocardial infarction. Direct thrombin inhibitors like Dabigatran offer therapeutic benefits but pose bleeding risks due to prolonged systemic availability.</p> Objective <p>This study investigates synthetic tripeptides as potential thrombin inhibitors, designed to mimic the Arg-Gly cleavage site in fibrinogen or the protease activated receptors 1 and 4 (PAR 1 and 4) of the platelets while incorporating nonstandard amino acids for enhanced stability and selectivity.</p> Methods <p>Synthetic tripeptides (RGH, RSH, RAH, RBH) were evaluated for their thrombin inhibition efficacy using in vitro, in silico, and in vivo analyses. Molecular docking, biochemical assays, platelet aggregation studies, and coagulation tests assessed their anticoagulant potential. Mouse models were used to determine efficacy in anticoagulation, thromboembolism prevention, and bleeding risks.</p> Results <p>The peptides effectively inhibited thrombin activity, reduced fibrinogenolysis, and delayed clot formation in a dose-dependent manner. Compared to Dabigatran, which remained active for 60&#xa0;h, these peptides were active for approximately 30&#xa0;h, reducing prolonged bleeding risks. In vivo studies confirmed their efficacy in preventing thrombin-induced pulmonary embolism without causing excessive bleeding.</p> Conclusion <p>These synthetic tripeptides exhibit promising thrombin inhibition capabilities and offer a safer alternative to long-acting anticoagulants. Their shorter activity duration may be beneficial in clinical scenarios requiring precise anticoagulation control.</p>

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Synthetic Peptide-Based Thrombin Inhibitors: a Potential Anticoagulant Approach

  • 期刊论文

  • 发表日期：

    2025年4月7日

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  • Supriya Sarkar,
  • Vilas Hiremath,
  • Muddegowda Umashankara,
  • Bannikuppe Sannanaik Vishwanath

摘要

Background

Hemostasis prevents excessive bleeding through clot formation; however, uncontrolled thrombin activity can lead to thrombosis-related conditions such as deep vein thrombosis and myocardial infarction. Direct thrombin inhibitors like Dabigatran offer therapeutic benefits but pose bleeding risks due to prolonged systemic availability.

Objective

This study investigates synthetic tripeptides as potential thrombin inhibitors, designed to mimic the Arg-Gly cleavage site in fibrinogen or the protease activated receptors 1 and 4 (PAR 1 and 4) of the platelets while incorporating nonstandard amino acids for enhanced stability and selectivity.

Methods

Synthetic tripeptides (RGH, RSH, RAH, RBH) were evaluated for their thrombin inhibition efficacy using in vitro, in silico, and in vivo analyses. Molecular docking, biochemical assays, platelet aggregation studies, and coagulation tests assessed their anticoagulant potential. Mouse models were used to determine efficacy in anticoagulation, thromboembolism prevention, and bleeding risks.

Results

The peptides effectively inhibited thrombin activity, reduced fibrinogenolysis, and delayed clot formation in a dose-dependent manner. Compared to Dabigatran, which remained active for 60 h, these peptides were active for approximately 30 h, reducing prolonged bleeding risks. In vivo studies confirmed their efficacy in preventing thrombin-induced pulmonary embolism without causing excessive bleeding.

Conclusion

These synthetic tripeptides exhibit promising thrombin inhibition capabilities and offer a safer alternative to long-acting anticoagulants. Their shorter activity duration may be beneficial in clinical scenarios requiring precise anticoagulation control.