https://scholars.lib.ntu.edu.tw/handle/123456789/503985
標題: | Structure-guided design of pure orthosteric inhibitors of αIIbβ3 that prevent thrombosis but preserve hemostasis | 作者: | Adair B.D. Alonso J.L. van Agthoven J. Hayes V. Ahn H.S. Yu I.-S. SHU-WHA LIN Xiong J.-P. Poncz M. Arnaout M.A. |
公開日期: | 2020 | 卷: | 11 | 期: | 1 | 起(迄)頁: | 398 | 來源出版物: | Nature Communications | 摘要: | A prevailing dogma is that inhibition of vascular thrombosis by antagonizing platelet integrin αIIbβ3 cannot be achieved without compromising hemostasis, thus causing serious bleeding and increased morbidity and mortality. It is speculated that these adverse outcomes result from drug-induced activating conformational changes in αIIbβ3 but direct proof is lacking. Here, we report the structure-guided design of peptide Hr10 and a modified form of the partial agonist drug tirofiban that act as “pure” antagonists of αIIbβ3, i.e., they no longer induce the conformational changes in αIIbβ3. Both agents inhibit human platelet aggregation but preserve clot retraction. Hr10 and modified tirofiban are as effective as partial agonist drugs in inhibiting vascular thrombosis in humanized mice, but neither causes serious bleeding, establishing a causal link between partial agonism and impaired hemostasis. Pure orthosteric inhibitors of αIIbβ3 may thus provide safer alternatives for human therapy, and valuable tools to probe structure–activity relationships in integrins. ? 2020, The Author(s). |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/503985 | ISSN: | 2041-1723 | DOI: | 10.1038/s41467-019-13928-2 | SDG/關鍵字: | eptifibatide; glycoprotein; hr10; integrin alpha2b beta3; monoclonal antibody; partial agonist; protein inhibitor; tirofiban; unclassified drug; antithrombocytic agent; fibrinogen receptor; peptide; tirofiban; von Willebrand factor; design method; gene; gene expression; homeostasis; inhibitor; protein; rodent; ultrastructure; affinity chromatography; animal experiment; animal model; antiplatelet activity; Article; blood clot retraction; carbon nuclear magnetic resonance; cell culture technique; conformational transition; controlled study; crystal structure; DNA sequencing; enzyme active site; gene expression; genetic transfection; genotyping technique; hemostasis; human; human cell; IC50; in vitro study; in vivo study; K-562 cell line; ligand binding; liquid chromatography-mass spectrometry; male; mouse; nonhuman; plasmid; platelet count; protein expression; protein modification; protein purification; proton nuclear magnetic resonance; real time polymerase chain reaction; Sanger sequencing; site directed mutagenesis; structure activity relation; tail bleeding time; thrombocyte aggregation; thrombosis; X ray crystallography; animal; bleeding; blood clotting; blood clotting parameters; chemistry; disease model; drug design; drug effect; gene knock-in; genetics; normal human; thrombocyte activation; thrombosis; transgenic mouse; Mus; Animals; Blood Coagulation; Disease Models, Animal; Drug Design; Gene Knock-In Techniques; Healthy Volunteers; Hemorrhage; Humans; K562 Cells; Male; Mice; Mice, Transgenic; Peptides; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Platelet Glycoprotein GPIIb-IIIa Complex; Structure-Activity Relationship; Thrombosis; Tirofiban; von Willebrand Factor |
顯示於: | 醫學檢驗暨生物技術學系 |
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