دورية أكاديمية
Enhanced EphB2-Specific Peptide Inhibitors through Stabilization of Polyproline II Helical Structure.
| العنوان: | Enhanced EphB2-Specific Peptide Inhibitors through Stabilization of Polyproline II Helical Structure. |
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| المؤلفون: | Tennett JC; Department of Chemistry, Fordham University, 441 E. Fordham Rd., Bronx, New York 10458, United States., Epstein SR; Department of Chemistry, Fordham University, 441 E. Fordham Rd., Bronx, New York 10458, United States., Sawyer N; Department of Chemistry, Fordham University, 441 E. Fordham Rd., Bronx, New York 10458, United States. |
| المصدر: | ACS chemical biology [ACS Chem Biol] 2024 Jun 21; Vol. 19 (6), pp. 1214-1221. Date of Electronic Publication: 2024 May 13. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 101282906 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1554-8937 (Electronic) Linking ISSN: 15548929 NLM ISO Abbreviation: ACS Chem Biol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, D.C. : American Chemical Society, c2006- |
| مواضيع طبية MeSH: | Receptor, EphB2*/chemistry , Receptor, EphB2*/metabolism , Receptor, EphB2*/antagonists & inhibitors , Peptides*/chemistry , Peptides*/pharmacology, Humans ; Molecular Dynamics Simulation ; Protein Binding |
| مستخلص: | Ephrin (Eph) receptors are the largest family of receptor tyrosine kinases. Interactions between Eph receptors and their membrane-bound ephrin protein ligands are associated with many developmental processes as well as various cancers and neurodegenerative diseases. With significant crosstalk between different Eph receptors and ephrin ligands, there is an urgent need for high-affinity ligands that bind specifically to individual Eph receptors to interrogate and modulate their functions. Here, we describe the rational development of potent EphB2 receptor inhibitors derived from the EphB2 receptor-specific SNEW peptide. To improve inhibitory potency, we evaluated 20+ cross-linkers with the goal of spanning and stabilizing a single polyproline II helical turn observed when SNEW binds to the EphB2 receptor. Of the cross-linkers evaluated, an 11-atom cross-linker, composed of a rigid 2,7-dimethylnaphthyl moiety between two cysteine residues, was found to yield the most potent inhibitor. Analysis of the cyclized region of this peptide by NMR and molecular dynamics simulations suggests that cross-linking stabilizes the receptor-bound polyproline II helix structure observed in the receptor-peptide complex. Cross-linked SNEW variants retained binding specificity for EphB2 and showed cross-linker-dependent resistance to trypsin proteolysis. Beyond the discovery of more potent EphB2 receptor inhibitors, these studies illustrate a novel cyclization approach with potential to stabilize polyproline II helical structure in various peptides for specific targeting of the myriad protein-protein interactions (PPIs) mediated by polyproline II helices. |
| المشرفين على المادة: | 25191-13-3 (polyproline) EC 2.7.10.1 (Receptor, EphB2) 0 (Peptides) EC 2.7.10.1 (EPHB2 protein, human) |
| تواريخ الأحداث: | Date Created: 20240513 Date Completed: 20240621 Latest Revision: 20240624 |
| رمز التحديث: | 20240624 |
| DOI: | 10.1021/acschembio.3c00791 |
| PMID: | 38739742 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1554-8937 |
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| DOI: | 10.1021/acschembio.3c00791 |