Sulfated pentagalloylglucoside is a potent, allosteric, and selective inhibitor of factor XIa.

Al-Horani RA, Ponnusamy P, Mehta AY, Gailani D, Desai UR
J Med Chem. 2013 56 (3): 867-78

PMID: 23316863 · PMCID: PMC3574227 · DOI:10.1021/jm301338q

Inhibition of factor XIa (FXIa) is a novel paradigm for developing anticoagulants without major bleeding consequences. We present the discovery of sulfated pentagalloylglucoside (6) as a highly selective inhibitor of human FXIa. Biochemical screening of a focused library led to the identification of 6, a sulfated aromatic mimetic of heparin. Inhibitor 6 displayed a potency of 551 nM against FXIa, which was at least 200-fold more selective than other relevant enzymes. It also prevented activation of factor IX and prolonged human plasma and whole blood clotting. Inhibitor 6 reduced V(MAX) of FXIa hydrolysis of chromogenic substrate without affecting the K(M), suggesting an allosteric mechanism. Competitive studies showed that 6 bound in the heparin-binding site of FXIa. No allosteric small molecule has been discovered to date that exhibits equivalent potency against FXIa. Inhibitor 6 is expected to open up a major route to allosteric FXIa anticoagulants with clinical relevance.

MeSH Terms (15)

Allosteric Regulation Carbohydrate Sequence Chromatography, Liquid Enzyme Activation Factor XIa Glucosides Hydrolysis Kinetics Magnetic Resonance Spectroscopy Molecular Mimicry Molecular Sequence Data Serine Proteinase Inhibitors Spectrometry, Mass, Electrospray Ionization Sulfuric Acid Esters Thrombelastography

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