Document Detail


Sulfated pentagalloylglucoside is a potent, allosteric, and selective inhibitor of factor XIa.
MedLine Citation:
PMID:  23316863     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Rami A Al-Horani; Pooja Ponnusamy; Akul Y Mehta; David Gailani; Umesh R Desai
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-28
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  56     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-15     Completed Date:  2013-04-19     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  867-78     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Allosteric Regulation
Carbohydrate Sequence
Chromatography, Liquid
Enzyme Activation
Factor XIa / antagonists & inhibitors*
Glucosides / chemistry,  pharmacology*
Hydrolysis
Kinetics
Magnetic Resonance Spectroscopy
Molecular Mimicry
Molecular Sequence Data
Serine Proteinase Inhibitors / chemistry,  pharmacology*
Spectrometry, Mass, Electrospray Ionization
Sulfuric Acid Esters / chemistry,  pharmacology*
Thrombelastography
Grant Support
ID/Acronym/Agency:
HL090586/HL/NHLBI NIH HHS; HL107152/HL/NHLBI NIH HHS; P01 HL107152/HL/NHLBI NIH HHS; R01 HL058837/HL/NHLBI NIH HHS; R01 HL081326/HL/NHLBI NIH HHS; R01 HL090586/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Glucosides; 0/Serine Proteinase Inhibitors; 0/Sulfuric Acid Esters; 0/sulfated pentagalloylglucoside; EC 3.4.21.27/Factor XIa
Comments/Corrections

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