ArticleCell2022
A general chemical principle for creating closure-stabilizing integrin inhibitors.
Article in Cell, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 58 citations in OpenAlex.
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- Conformational Preference Classification of Integrin-Binding Ligands Using Free Energy Perturbation.JACS Au · 2026Article
- Multi-omics elucidation of recombinant collagen-mediated modulation of mesenchymal stem cell functions.Journal of advanced research · 2026Article
- Structural basis for the differential recognition of integrin αvβ3 by rhodostomin and trimucrin.Communications biology · 2026Article
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- PYGO1 drives gastric cancer progression via the ITGB1/CD47 axis and is therapeutically targeted by pentagalloylglucose.Journal of translational medicine · 2025Article
- Shared ligand-blocking mechanism but distinct conformational modulation by α5-targeting antibodies BIIG2 and MINT1526A.bioRxiv : the preprint server for biology · 2025Article
- Therapeutic Prospects of αv Integrins Inhibition in Fibrotic Lung Diseases and Carcinogenesis.International journal of molecular sciences · 2025Review
- Exploring Integrin α5β1 as a Potential Therapeutic Target for Pulmonary Arterial Hypertension: Insights From Comprehensive Multicenter Preclinical Studies.Circulation · 2025Article
- The Integrin Receptors: From Discovery to Structure to Medicines.Immunological reviews · 2025Review
- Embedding a commitment to equitable global access into basic and early-phase translational research.Journal of clinical and translational science · 2025Review
- Autoantibodies immuno-mechanically modulate platelet contractile force and bleeding risk.Nature communications · 2024Article
- Multi-parametric thrombus profiling microfluidics detects intensified biomechanical thrombogenesis associated with hypertension and aging.Nature communications · 2024Article
- Platelet integrin αIIbβ3 plays a key role in a venous thrombogenesis mouse model.Nature communications · 2024Article
- 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
- Multi-parametric thrombus profiling microfluidics detects intensified biomechanical thrombogenesis associated with hypertension and aging.bioRxiv : the preprint server for biology · 2024Article
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Integrins are validated drug targets with six approved therapeutics. However, small-molecule inhibitors to three integrins failed in late-stage clinical trials for chronic indications. Such unfavorable outcomes may in part be caused by partial agonism, i.e., the stabilization of the high-affinity, extended-open integrin conformation. Here, we show that the failed, small-molecule inhibitors of integrins αIIbβ3 and α4β1 stabilize the high-affinity conformation. Furthermore, we discovered a simple chemical feature present in multiple αIIbβ3 antagonists that stabilizes integrins in their bent-closed conformation. Closing inhibitors contain a polar nitrogen atom that stabilizes, via hydrogen bonds, a water molecule that intervenes between a serine residue and the metal in the metal-ion-dependent adhesion site (MIDAS). Expulsion of this water is a requisite for transition to the open conformation. This change in metal coordination is general to integrins, suggesting broad applicability of the drug-design principle to the integrin family, as validated with a distantly related integrin, α4β1.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.