ArticleScience translational medicine2012
Structure-guided design of a high-affinity platelet integrin αIIbβ3 receptor antagonist that disrupts Mg²⁺ binding to the MIDAS.
Article in Science translational medicine, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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Who cites it
61 citing papers in PubMed, 94 citations in OpenAlex.
- Pharmacokinetics, pharmacodynamics, and tolerability of subcutaneous administration of a novel glycoprotein IIb/IIIa inhibitor, RUC-4, in patients with ST-segment elevation myocardial infarction.EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology · 2021Trial
- First Human Use of RUC-4: A Nonactivating Second-Generation Small-Molecule Platelet Glycoprotein IIb/IIIa (Integrin αIIbβ3) Inhibitor Designed for Subcutaneous Point-of-Care Treatment of ST-Segment-Elevation Myocardial Infarction.Journal of the American Heart Association · 2020Trial
- Selective inhibition of platelet inflammatory tether formation via force-modulated vibrational states of integrin αIIbβ3.Journal of molecular modeling · 2026Article
- A monoclonal antibody to platelet αIIbβ3 that inhibits protein disulfide isomerase binding and platelet aggregation.Blood advances · 2026Article
- Frame-Shifted Synthesis of Oligoheterocycles as a Platform for Molecular Design.Angewandte Chemie (International ed. in English) · 2026Article
- Prediction of αBiophysical journal · 2025Article
- MnBiophysical journal · 2025Article
- An αIIbβ3 ligand-mimetic murine monoclonal antibody that produces platelet activation by engaging the FcγIIa receptor.Blood advances · 2025Article
- The Integrin Receptors: From Discovery to Structure to Medicines.Immunological reviews · 2025Review
- Structural insights into the molecular recognition of integrin αVβ3 by RGD-containing ligands: The role of the specificity-determining loop (SDL).bioRxiv : the preprint server for biology · 2024Article
- Current and Future Roles of Glycoprotein IIb-IIIa Inhibitors in Primary Angioplasty for ST-Segment Elevation Myocardial Infarction.Biomedicines · 2024Review
- Application of Funnel Metadynamics to the Platelet Integrin αIIbβ3 in Complex with an RGD Peptide.International journal of molecular sciences · 2024Article
- Integrins as Drug Targets in Vascular and Related Diseases.International journal of drug discovery and pharmacology · 2024Article
- Electrolyte Imbalance and Neurologic Injury.CNS & neurological disorders drug targets · 2024Review
- Development of the Integrated Computer Simulation Model of the Intracellular, Transmembrane, and Extracellular Domain of Platelet Integrin αTH open : companion journal to thrombosis and haemostasis · 2024Article
- Critical Analysis of Thrombocytopenia Associated With Glycoprotein IIb/IIIa Inhibitors and Potential Role of Zalunfiban, a Novel Small Molecule Glycoprotein Inhibitor, in Understanding the Mechanism(s).Journal of the American Heart Association · 2023Review
- Cryo-EM structures of full-length integrin αIIbβ3 in native lipids.Nature communications · 2023Article
- Prehospital treatment with zalunfiban (RUC-4) in patients with ST- elevation myocardial infarction undergoing primary percutaneous coronary intervention: Rationale and design of the CELEBRATE trial.American heart journal · 2023Article
- Targeting integrin pathways: mechanisms and advances in therapy.Signal transduction and targeted therapy · 2023Review
- Novel strategies in antithrombotic therapy: targeting thrombosis while preserving hemostasis.Frontiers in cardiovascular medicine · 2023Review
1 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 4 institutions in 1 country.
Funding
Abstract
An integrin found on platelets, α(IIb)β(3) mediates platelet aggregation, and α(IIb)β(3) antagonists are effective antithrombotic agents in the clinic. Ligands bind to integrins in part by coordinating a magnesium ion (Mg(2+)) located in the β subunit metal ion-dependent adhesion site (MIDAS). Drugs patterned on the integrin ligand sequence Arg-Gly-Asp have a basic moiety that binds the α(IIb) subunit and a carboxyl group that coordinates the MIDAS Mg(2+) in the β(3) subunits. They induce conformational changes in the β(3) subunit that may have negative consequences such as exposing previously hidden epitopes and inducing the active conformation of the receptor. We recently reported an inhibitor of α(IIb)β(3) (RUC-1) that binds exclusively to the α(IIb) subunit; here, we report the structure-based design and synthesis of RUC-2, a RUC-1 derivative with a ~100-fold higher affinity. RUC-2 does not induce major conformational changes in β(3) as judged by monoclonal antibody binding, light scattering, gel chromatography, electron microscopy, and a receptor priming assay. X-ray crystallography of the RUC-2-α(IIb)β(3) headpiece complex in 1 mM calcium ion (Ca(2+))/5 mM Mg(2+) at 2.6 Å revealed that RUC-2 binds to α(IIb) the way RUC-1 does, but in addition, it binds to the β(3) MIDAS residue glutamic acid 220, thus displacing Mg(2+) from the MIDAS. When the Mg(2+) concentration was increased to 20 mM, however, Mg(2+) was identified in the MIDAS and RUC-2 was absent. RUC-2's ability to inhibit ligand binding and platelet aggregation was diminished by increasing the Mg(2+) concentration. Thus, RUC-2 inhibits ligand binding by a mechanism different from that of all other α(IIb)β(3) antagonists and may offer advantages as a therapeutic agent.
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