A novel alpha iIb beta 3 antagonist from snake venom prevents thrombosis without causing bleeding
Journal
Toxins
Journal Volume
12
Journal Issue
1
Pages
11
Date Issued
2019
Author(s)
Abstract
Life-threatening thrombocytopenia and bleeding, common side effects of clinically available αIIbβ3 antagonists, are associated with the induction of ligand-induced integrin conformational changes and exposure of ligand-induced binding sites (LIBSs). To address this issue, we examined intrinsic mechanisms and structure-activity relationships of purified disintegrins, from Protobothrops flavoviridis venom (i.e., Trimeresurus flavoviridis), TFV-1 and TFV-3 with distinctly different pro-hemorrhagic tendencies. TFV-1 with a different αIIbβ3 binding epitope from that of TFV-3 and chimeric 7 × 103 Fab, i.e., Abciximab, decelerates αIIbβ33 ligation without causing a conformational change in αIIbβ3, as determined with the LIBS antibody, AP5, and the mimetic, drug-dependent antibody (DDAb), AP2, an inhibitory monoclonal antibody raised against αIIbβ33. Consistent with their different binding epitopes, a combination of TFV-1 and AP2 did not induce FcγRIIa-mediated activation of the ITAM-Syk-PLCγ2 pathway and platelet aggregation, in contrast to the clinical antithrombotics, abciximab, eptifibatide, and disintegrin TFV-3. Furthermore, TFV-1 selectively inhibits Gα13-mediated platelet aggregation without affecting talin-driven clot firmness, which is responsible for physiological hemostatic processes. At equally efficacious antithrombotic dosages, TFV-1 caused neither severe thrombocytopenia nor bleeding in FcγRIIa-transgenic mice. Likewise, it did not induce hypocoagulation in human whole blood in the rotational thromboelastometry (ROTEM) assay used in perioperative situations. In contrast, TFV-3 and eptifibatide exhibited all of these hemostatic effects. Thus, the αIIbβ3 antagonist, TFV-1, efficaciously prevents arterial thrombosis without adversely affecting hemostasis. ? 2019 by the authors.
Subjects
Antiplatelet agent; Arterial thrombosis; Bleeding side effect; Disintegrins; Integrin αIIbβ3; Snake venom proteins
SDGs
Other Subjects
abciximab; adenine nucleotide translocase; adenosine diphosphate; alpha2 integrin; collagen; disintegrin; eptifibatide; G protein coupled receptor; L selectin; monoclonal antibody; monoclonal antibody ap2; PADGEM protein; snake venom; tetrapeptide; thrombin; Trimeresurus ?avoviridis venom 1; Trimeresurus ?avoviridis venom 3; unclassified drug; abciximab; antithrombocytic agent; disintegrin; epitope; fibrinogen receptor; fibrinolytic agent; snake venom; animal experiment; animal model; Article; binding site; bleeding; bleeding time; blood clotting; blood clotting time; chromatography; column chromatography; controlled study; flow cytometry; gene sequence; hemostasis; high performance liquid chromatography; human; IC50; immunoprecipitation; ligand binding; liquid chromatography; mass spectrometry; matrix assisted laser desorption ionization time of flight mass spectrometry; mouse; nonhuman; pharmacokinetic parameters; platelet count; polyacrylamide gel electrophoresis; protein phosphorylation; Protobothrops ?avoviridis; reversed phase high performance liquid chromatography; structure activity relation; suicide; tandem mass spectrometry; thrombocyte activation; thrombocyte aggregation; thrombocyte function; thrombocyte rich plasma; thrombocytopenia; thrombosis; Western blotting; animal; bleeding; Institute for Cancer Research mouse; male; Trimeresurus; Abciximab; Animals; Binding Sites; Bleeding Time; Disintegrins; Epitopes; Fibrinolytic Agents; Hemorrhage; Humans; Male; Mice; Mice, Inbred ICR; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Snake Venoms; Structure-Activity Relationship; Trimeresurus
Type
journal article