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2000
Volume 21, Issue 19
  • ISSN: 1570-1808
  • E-ISSN: 1875-628X

Abstract

Background

Activated Protein C (APC) is a plasma serine protease with antithrombotic function. APC acts as an anticoagulant by promoting the degradation of factors Va and VIIIa, thus inhibiting the formation of thrombin. Specific inhibition of APC has been proposed to benefit hemophilia therapy.

Methods

We used chromogenic tripeptide substrate hydrolysis assay to screen a series of arginine and arginine-like containing small molecules to identify inhibitors of APC. Similar hydrolysis assays were used to determine selectivity against other serine proteases and blood-clotting enzymes. Molecular modeling was exploited to illustrate the binding of the most potent and selective inhibitor onto the putative binding site.

Results

We identified inhibitor as a potent inhibitor with an value of 1.1 µM. The molecule demonstrated >100-fold selectivity against thrombin, factor XIa, and neutrophil elastase, >50-fold selectivity against factor XIIIa, 10-fold selectivity against factor Xa, and 8-fold selectivity against human plasmin. Molecular modeling reveals that inhibitor binds to the active site of APC with the best-docked structure, indicating that one protonated amidino group establishes a salt bridge to the side chain carboxylate of Asp189 residue. Another inhibitor was identified, yet it was not as selective to APC. Importantly, inhibitor demonstrates favorable physicochemical, pharmacokinetic, and drug-likeness properties.

Conclusion

Inhibitor is a selective and potent inhibitor of APC that serves as a powerful lead for the development of hemophilia therapy.

© 2024 Bentham Science Publishers
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2025-03-07
2025-08-16

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Discovery of New Inhibitors of Human Activated Protein C to Treat Hemophilia
Letters in Drug Design & Discovery 21, 4919 (2024); https://doi.org/10.2174/0115701808340492250115102419
/content/journals/lddd/10.2174/0115701808340492250115102419
/content/journals/lddd/10.2174/0115701808340492250115102419
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  • Article Type:     Research Article
Keyword(s): activated protein C; active site inhibitor; amidine; arginine-like; clotting; Hemophilia; serine protease

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