Allosteric inhibition of human factor XIa: discovery of monosulfated benzofurans as a class of promising inhibitors.

ABSTRACT: Factor XIa (fXIa) is being recognized as a prime target for developing safer anticoagulants. To discover synthetic, small, allosteric inhibitors of fXIa, we screened an in-house, unique library of 65 molecules displaying many distinct scaffolds and varying levels of sulfation. Of these, monosulfated benzofurans were the only group of molecules found to inhibit fXIa (?100% efficacy) and led to the identification of monosulfated trimer 24 (IC50 0.82 ?M) as the most potent inhibitor. Michaelis-Menten kinetics studies revealed a classic noncompetitive mechanism of action for 24. Although monosulfated, the inhibitors did not compete with unfractionated heparin alluding to a novel site of interaction. Fluorescence quenching studies indicated that trimer 24 induces major conformational changes in the active site of fXIa. Docking studies identified a site near Lys255 on the A3 domain of fXIa as the most probable site of binding for 24. Factor XIa devoid of the A3 domain displayed a major defect in the inhibition potency of 24 supporting the docking prediction. Our work presents the sulfated benzofuran scaffold as a promising framework to develop allosteric fXIa inhibitors that likely function through the A3 domain.

SUBMITTER: Argade MD 

PROVIDER: S-EPMC4317055 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature