Al-Horani RA, Ponnusamy P, Mehta AY, Gailani D, Desai UR. (2013) Sulfated Pentagalloylglucoside Is a Potent, Allosteric, and Selective Inhibitor of Factor XIa. J Med Chem. 56(3):867-78. PMID: 23316863; PMCID: PMC3574227
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.
Link to journal: http://pubs.acs.org/journal/jmcmar