دورية أكاديمية
أعرض في EDS

Notch1 and Notch4 core binding domain peptibodies exhibit distinct ligand-binding and anti-angiogenic properties.

التفاصيل البيبلوغرافية
العنوان: Notch1 and Notch4 core binding domain peptibodies exhibit distinct ligand-binding and anti-angiogenic properties.
المؤلفون: Sargis T; Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL, 60612, USA., Youn SW; Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL, 60612, USA., Thakkar K; Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL, 60612, USA., Naiche LA; Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL, 60612, USA., Paik NY; Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL, 60612, USA., Pajcini KV; Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL, 60612, USA.; University of Illinois Cancer Center, University of Illinois Chicago, Chicago, IL, 60612, USA., Kitajewski JK; Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL, 60612, USA. kitaj@uic.edu.; University of Illinois Cancer Center, University of Illinois Chicago, Chicago, IL, 60612, USA. kitaj@uic.edu.
المصدر: Angiogenesis [Angiogenesis] 2023 May; Vol. 26 (2), pp. 249-263. Date of Electronic Publication: 2022 Nov 15.
نوع المنشور: Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: Springer Country of Publication: Germany NLM ID: 9814575 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1573-7209 (Electronic) Linking ISSN: 09696970 NLM ISO Abbreviation: Angiogenesis Subsets: MEDLINE
أسماء مطبوعة: Publication: Dec. 2004- : Berlin : Springer
Original Publication: London ; Philadelphia : Rapid Science Publishers,
مواضيع طبية MeSH: Angiogenesis Inhibitors*/genetics , Angiogenesis Inhibitors*/metabolism , Angiogenesis Inhibitors*/pharmacology , Endothelial Cells*/drug effects , Endothelial Cells*/metabolism , Receptor, Notch1*/antagonists & inhibitors , Receptor, Notch1*/genetics , Receptor, Notch1*/metabolism , Receptor, Notch4*/genetics , Receptor, Notch4*/metabolism, Animals ; Mice ; Epidermal Growth Factor/metabolism ; Immunoprecipitation ; Inflammation/drug therapy ; Inflammation/genetics ; Inflammation/metabolism ; Ligands ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/metabolism ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/metabolism ; Retinal Vessels/drug effects ; Surface Plasmon Resonance
مستخلص: The Notch signaling pathway is an important therapeutic target for the treatment of inflammatory diseases and cancer. We previously created ligand-specific inhibitors of Notch signaling comprised of Fc fusions to specific EGF-like repeats of the Notch1 extracellular domain, called Notch decoys, which bound ligands, blocked Notch signaling, and showed anti-tumor activity with low toxicity. However, the study of their function depended on virally mediated expression, which precluded dosage control and limited clinical applicability. We have refined the decoy design to create peptibody-based Notch inhibitors comprising the core binding domains, EGF-like repeats 10-14, of either Notch1 or Notch4. These Notch peptibodies showed high secretion properties and production yields that were improved by nearly 100-fold compared to previous Notch decoys. Using surface plasmon resonance spectroscopy coupled with co-immunoprecipitation assays, we observed that Notch1 and Notch4 peptibodies demonstrate strong but distinct binding properties to Notch ligands DLL4 and JAG1. Both Notch1 and Notch4 peptibodies interfere with Notch signaling in endothelial cells and reduce expression of canonical Notch targets after treatment. While prior DLL4 inhibitors cause hyper-sprouting, the Notch1 peptibody reduced angiogenesis in a 3-dimensional in vitro sprouting assay. Administration of Notch1 peptibodies to neonate mice resulted in reduced radial outgrowth of retinal vasculature, confirming anti-angiogenic properties. We conclude that purified Notch peptibodies comprising EGF-like repeats 10-14 bind to both DLL4 and JAG1 ligands and exhibit anti-angiogenic properties. Based on their secretion profile, unique Notch inhibitory activities, and anti-angiogenic properties, Notch peptibodies present new opportunities for therapeutic Notch inhibition.
(© 2022. The Author(s).)
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معلومات مُعتمدة: R01 HL112626 United States HL NHLBI NIH HHS; R01 HL134971 United States HL NHLBI NIH HHS; T32 HL144459 United States HL NHLBI NIH HHS; R01 HL151720 United States HL NHLBI NIH HHS
فهرسة مساهمة: Keywords: Angiogenesis; Inhibitor; Notch; Notch core binding domain; Peptibody
المشرفين على المادة: 0 (Angiogenesis Inhibitors)
0 (DLL4 protein, mouse)
62229-50-9 (Epidermal Growth Factor)
0 (Jag1 protein, mouse)
0 (Ligands)
0 (Notch1 protein, mouse)
146991-60-8 (Notch4 protein, mouse)
0 (Receptor, Notch1)
0 (Receptor, Notch4)
0 (Recombinant Fusion Proteins)
تواريخ الأحداث: Date Created: 20221115 Date Completed: 20230426 Latest Revision: 20231003
رمز التحديث: 20231003
مُعرف محوري في PubMed: PMC10119233
DOI: 10.1007/s10456-022-09861-6
PMID: 36376768
قاعدة البيانات: MEDLINE
الوصف
تدمد:1573-7209
DOI:10.1007/s10456-022-09861-6