title: Sulfated pentagalloylglucoside is a potent, allosteric, and selective inhibitor of factor XIa.
abstract: 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.
authors: Department of Medicinal Chemistry and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia 23219, USA.
authors: Rami A
authors: RA
authors: Al-Horani
authors: Pooja
authors: P
authors: Ponnusamy
authors: Akul Y
authors: AY
authors: Mehta
authors: David
authors: D
authors: Gailani
authors: Umesh R
authors: UR
authors: Desai
mesh_terms: D000494:Allosteric Regulation; D002240:Carbohydrate Sequence; D002853:Chromatography, Liquid; D004789:Enzyme Activation; D015945:Factor XIa / Q000037:antagonists & inhibitors*; D005960:Glucosides / Q000737:chemistry / Q000494:pharmacology*; D006868:Hydrolysis; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013463:Sulfuric Acid Esters / Q000737:chemistry / Q000494:pharmacology*; D013916:Thrombelastography
chemical_list: D005960:Glucosides; D015842:Serine Proteinase Inhibitors; D013463:Sulfuric Acid Esters; C579812:sulfated pentagalloylglucoside; D015945:Factor XIa