title: Allosterism-based simultaneous, dual anticoagulant and antiplatelet action: allosteric inhibitor targeting the glycoprotein Ibα-binding and heparin-binding site of thrombin.
abstract: BACKGROUND
  Allosteric inhibition is a promising approach for developing a new group of anticoagulants with potentially reduced bleeding consequences. Recently, we designed sulfated β-O4 lignin (SbO4L) as an allosteric inhibitor that targets exosite 2 of thrombin to reduce fibrinogen cleavage through allostery and compete with glycoprotein Ibα to reduce platelet activation.
  
  
  OBJECTIVE
  To assess: (i) the antithrombotic potential of a novel approach of simultaneous exosite 2-dependent allosteric inhibition of thrombin and competitive inhibition of platelet activation; and (ii) the promise of SbO4L as the first-in-class antithrombotic agent.
  
  
  METHODS
  A combination of whole blood thromboelastography, hemostasis analysis, mouse arterial thrombosis models and mouse tail bleeding studies were used to assess antithrombotic potential.
  
  
  CONCLUSIONS
  SbO4L extended the clot initiation time, and reduced maximal clot strength, platelet contractile force, and the clot elastic modulus, suggesting dual anticoagulant and antiplatelet effects. These effects were comparable to those observed with enoxaparin. A dose of 1 mg of SbO4L per mouse prevented occlusion in 100% of arteries, and lower doses resulted in a proportionally reduced response. Likewise, the time to occlusion increased by ~ 70% with a 0.5-mg dose in the mouse Rose Bengal thrombosis model. Finally, tail bleeding studies demonstrated that SbO4L does not increase bleeding propensity. In comparison, a 0.3-mg dose of enoxaparin increased the bleeding time and blood volume loss. Overall, this study highlights the promise of the allosteric inhibition approach, and presents SbO4L as a novel anticoagulant with potentially reduced bleeding side effects.
authors.affiliation: Department of Medicinal Chemistry and Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: A Y
authors.initials: AY
authors.lastname: Mehta
authors.affiliation: Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, VA, USA.|Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
authors.forename: B M
authors.initials: BM
authors.lastname: Mohammed
authors.affiliation: Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Martin
authors.affiliation: Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: D F
authors.initials: DF
authors.lastname: Brophy
authors.affiliation: Department of Pathology, Immunology and Microbiology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: D
authors.initials: D
authors.lastname: Gailani
authors.affiliation: Department of Medicinal Chemistry and Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: U R
authors.initials: UR
authors.lastname: Desai
mesh_terms: D000495:Allosteric Site; D000818:Animals; D000925:Anticoagulants / Q000737:chemistry*; D001665:Binding Sites; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests; D003198:Computer Simulation; D017984:Enoxaparin / Q000494:pharmacology; D005343:Fibrinolytic Agents / Q000737:chemistry; D006470:Hemorrhage; D006487:Hemostasis; D006493:Heparin / Q000627:therapeutic use; D006801:Humans; D006868:Hydrolysis; D008031:Lignin / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D015539:Platelet Activation; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry*; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000737:chemistry*; D053657:Platelet-Rich Plasma; D011485:Protein Binding; D012306:Risk; D013916:Thrombelastography; D013917:Thrombin / Q000737:chemistry* / Q000276:immunology; D013927:Thrombosis
chemical_list: D000925:Anticoagulants; D017984:Enoxaparin; D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D019038:Platelet Glycoprotein GPIb-IX Complex; D006493:Heparin; D008031:Lignin; D013917:Thrombin
keywords: allosteric regulation; anticoagulant agents; antiplatelet agents; blood coagulation; glycoprotein Ib; thrombin