title: Potent, Selective, Allosteric Inhibition of Human Plasmin by Sulfated Non-Saccharide Glycosaminoglycan Mimetics.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, and Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University , Richmond, Virginia 23219, United States.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Afosah
authors.affiliation: Department of Medicinal Chemistry, and Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University , Richmond, Virginia 23219, United States.
authors.forename: Rami A
authors.initials: RA
authors.lastname: Al-Horani
authors.affiliation: Department of Medicinal Chemistry, and Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University , Richmond, Virginia 23219, United States.
authors.forename: Nehru Viji
authors.identifier: 0000-0002-2870-9164
authors.initials: NV
authors.lastname: Sankaranarayanan
authors.affiliation: Department of Medicinal Chemistry, and Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University , Richmond, Virginia 23219, United States.
authors.forename: Umesh R
authors.identifier: 0000-0002-1976-6597
authors.initials: UR
authors.lastname: Desai
mesh_terms: D044946:Biflavonoids / Q000138:chemical synthesis / Q000494:pharmacology*; D020134:Catalytic Domain; D005341:Fibrinolysin / Q000037:antagonists & inhibitors*; D005342:Fibrinolysis / Q000187:drug effects; D006025:Glycosaminoglycans / Q000737:chemistry*; D006493:Heparin / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D018716:Molecular Mimicry; D011479:Protamines / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013463:Sulfuric Acid Esters / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D044946:Biflavonoids; D006025:Glycosaminoglycans; D011479:Protamines; D015842:Serine Proteinase Inhibitors; D013463:Sulfuric Acid Esters; D006493:Heparin; D005341:Fibrinolysin