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Novel Scaffolds For Inducing Allosteric Inhibition of Coagulation Enzymes
Author(s) -
Desai Umesh R
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.676.6
Subject(s) - dhps , chemistry , allosteric regulation , sulfation , thrombin , discovery and development of direct thrombin inhibitors , hemostasis , pharmacology , coagulation , potency , biochemistry , enzyme , in vitro , biology , platelet , immunology , medicine , plasmodium falciparum , psychiatry , malaria
We have discovered novel scaffolds, called sulfated DHPs, which possess very interesting anticoagulant properties. In clotting assays, sulfated DHPs prolong PT at concentrations 2‐6‐fold below that of the clinically used LMWH enoxaparin, while in the APTT assay they required 2‐6‐fold higher concentration. Whole blood studies using thromboelastography and hemostasis analysis system reveal that sulphated DHPs inhibit clotting with potency only 18‐30‐fold weaker than enoxaparin. The new anticoagulants inhibit thrombin and factors Xa and XIa of the coagulation cascade with nM potency. Mechanistically, this potent inhibition arises primarily from direct inhibition of the enzymes through an allosteric disruption of the catalytic apparatus. Competitive binding studies show that the sulfated DHPs interact with exosite II of thrombin, a site not known to be associated with inhibition. Studies using A549 lung and HepG2 liver cell lines show no induction of toxicity by sulfated DHPs at concentrations as high as 50 mg/L. Rational drug design based on the sulphated DHP scaffold led to the synthesis of a small sulfated molecule, which exhibits good inhibition of thrombin & factor Xa. The novel mechanism of action and the new scaffold of these molecules suggest a strong possibility for discovering new therapeutically effective structures.