Allosteric Inhibition of Human Factor XIa: Discovery of Monosulfated Benzofurans as a Class of Promising Inhibitors

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• 作者：Malaika D. Argade ; Akul Y. Mehta ; Aurijit Sarkar ; Umesh R. Desai
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：April 24, 2014
• 年：2014
• 卷：57
• 期：8
• 页码：3559-3569
• 全文大小：643K
• 年卷期：v.57,no.8(April 24, 2014)
• ISSN：1520-4804

文摘

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 渭M) as the most potent inhibitor. Michaelis鈥揗enten 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.