Afosah Daniel K, Al-Horani Rami A, Sankaranarayanan Nehru Viji, Desai Umesh R
Department of Medicinal Chemistry, and Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University , Richmond, Virginia 23219, United States.
J Med Chem. 2017 Jan 26;60(2):641-657. doi: 10.1021/acs.jmedchem.6b01474. Epub 2017 Jan 5.
Although plasmin inhibitors could be used in multiple disorders, their use has been restricted to preventing blood loss in hemostatic dysregulation because of poor efficacy and adverse effects of current agents. We reasoned that a new class of direct inhibitors that offer better efficacy, selectivity, and safety could be discovered by exploiting allosterism in plasmin, a protease homologous to other allosteric serine proteases. We report on the synthesis, biological activity, and mechanism of action of a group of small molecules, called non-saccharide glycosaminoglycan mimetics (NSGMs), as direct allosteric plasmin inhibitors. Our results show that distinct NSGMs selectively inhibit human full-length plasmin. The molecule inhibited clot lysis, alluding to its promise as an allosteric regulator of plasmin. We show that direct allosteric inhibition of plasmin could led to new antifibrinolytic agent(s) that may exhibit better efficacy, potency, selectivity, and safety in comparison to current therapy.
尽管纤溶酶抑制剂可用于多种疾病，但由于现有药物疗效不佳和不良反应，其应用仅限于在止血功能失调时预防失血。我们推测，通过利用纤溶酶（一种与其他别构丝氨酸蛋白酶同源的蛋白酶）中的别构作用，有可能发现一类具有更好疗效、选择性和安全性的新型直接抑制剂。我们报告了一组称为非糖糖胺聚糖模拟物（NSGMs）的小分子作为直接别构纤溶酶抑制剂的合成、生物活性及作用机制。我们的结果表明，不同的NSGMs可选择性抑制人全长纤溶酶。该分子抑制凝块溶解，暗示其作为纤溶酶别构调节剂的潜力。我们表明，对纤溶酶的直接别构抑制可能会产生新的抗纤溶药物，与现有疗法相比，这些药物可能具有更好的疗效、效力、选择性和安全性。
