ArticleScientific reports2016
Allosteric Partial Inhibition of Monomeric Proteases. Sulfated Coumarins Induce Regulation, not just Inhibition, of Thrombin.
Article in Scientific reports, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 36 citations in OpenAlex.
- Fully Synthetic Non-Carbohydrate Heparin Mimetics-Perspectives for Therapeutic Anticoagulation and Beyond?Archiv der Pharmazie · 2026Review
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- Regulation of Peptidase Activity beyond the Active Site in Human Health and Disease.International journal of molecular sciences · 2023Review
- Partial Reversible Inhibition of Enzymes and Its Metabolic and Pharmaco-Toxicological Implications.International journal of molecular sciences · 2023Review
- Designing Smaller, Synthetic, Functional Mimetics of Sulfated Glycosaminoglycans as Allosteric Modulators of Coagulation Factors.Journal of medicinal chemistry · 2023Review
- Biomolecular interactions of ultrasmall metallic nanoparticles and nanoclusters.Nanoscale advances · 2021Review
- Studies on fragment-based design of allosteric inhibitors of human factor XIa.Bioorganic & medicinal chemistry · 2020Article
- Discovery of Benzyl Tetraphosphonate Derivative as Inhibitor of Human Factor Xia.ChemistryOpen · 2020Article
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- Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma.ACS medicinal chemistry letters · 2020Article
- Sulfated Non-Saccharide Glycosaminoglycan Mimetics as Novel Drug Discovery Platform for Various Pathologies.Current medicinal chemistry · 2020Review
- A synthetic heparin mimetic that allosterically inhibits factor XIa and reduces thrombosis in vivo without enhanced risk of bleeding.Journal of thrombosis and haemostasis : JTH · 2019Article
- On the Process of Discovering Leads That Target the Heparin-Binding Site of Neutrophil Elastase in the Sputum of Cystic Fibrosis Patients.Journal of medicinal chemistry · 2019Article
- Allosteric inhibition of α-thrombin enzymatic activity with ultrasmall gold nanoparticles.Nanoscale advances · 2019Article
- Phytochemical and Analytical Characterization of Novel Sulfated Coumarins in the Marine Green MacroalgaMolecules (Basel, Switzerland) · 2018Article
- Recent advances in the discovery and development of factor XI/XIa inhibitors.Medicinal research reviews · 2018Review
- A small group of sulfated benzofurans induces steady-state submaximal inhibition of thrombin.Bioorganic & medicinal chemistry letters · 2018Article
- Potent, Selective, Allosteric Inhibition of Human Plasmin by Sulfated Non-Saccharide Glycosaminoglycan Mimetics.Journal of medicinal chemistry · 2017Article
- Article
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5 authors at 1 institution in 1 country.
Funding
Abstract
Allosteric partial inhibition of soluble, monomeric proteases can offer major regulatory advantages, but remains a concept on paper to date; although it has been routinely documented for receptors and oligomeric proteins. Thrombin, a key protease of the coagulation cascade, displays significant conformational plasticity, which presents an attractive opportunity to discover small molecule probes that induce sub-maximal allosteric inhibition. We synthesized a focused library of some 36 sulfated coumarins to discover two agents that display sub-maximal efficacy (~50%), high potency (<500 nM) and high selectivity for thrombin (>150-fold). Michaelis-Menten, competitive inhibition, and site-directed mutagenesis studies identified exosite 2 as the site of binding for the most potent sulfated coumarin. Stern-Volmer quenching of active site-labeled fluorophore suggested that the allosteric regulators induce intermediate structural changes in the active site as compared to those that display ~80-100% efficacy. Antithrombin inactivation of thrombin was impaired in the presence of the sulfated coumarins suggesting that allosteric partial inhibition arises from catalytic dysfunction of the active site. Overall, sulfated coumarins represent first-in-class, sub-maximal inhibitors of thrombin. The probes establish the concept of allosteric partial inhibition of soluble, monomeric proteins. This concept may lead to a new class of anticoagulants that are completely devoid of bleeding.
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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.