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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Vanderslice, Peter Warier, Navin D. Dixon, Richard A. F. Caivano, Amy R. Willerson, James T. Woodside, Darren G. Gundlach, C. William Mcintyre, Bradley W. Bornmann, William G. Maxwell, David S. Khounlo, Sayadeth Brown, Wells S. Biediger, Ronald J. |
| Description | Author Affiliation: Vanderslice P ( Department of Molecular Cardiology, Texas Heart Institute at St. Luke's Episcopal Hospital, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.) |
| Abstract | Activation of the integrin family of cell adhesion receptors on progenitor cells may be a viable approach to enhance the effects of stem cell-based therapies by improving cell retention and engraftment. Here, we describe the synthesis and characterization of the first small molecule agonist identified for the integrin 4ß1 (also known as very late antigen-4 or VLA-4). The agonist, THI0019, was generated via two structural modifications to a previously identified 4ß1 antagonist. THI0019 greatly enhanced the adhesion of cultured cell lines and primary progenitor cells to 4ß1 ligands VCAM-1 and CS1 under both static and flow conditions. Furthermore, THI0019 facilitated the rolling and spreading of cells on VCAM-1 and the migration of cells toward SDF-1 . Molecular modeling predicted that the compound binds at the /ß subunit interface overlapping the ligand-binding site thus indicating that the compound must be displaced upon ligand binding. In support of this model, an analog of THI0019 modified to contain a photoreactive group was used to demonstrate that when cross-linked to the integrin, the compound behaves as an antagonist instead of an agonist. In addition, THI0019 showed cross-reactivity with the related integrin 4ß7 as well as 5ß1 and Lß2. When cross-linked to Lß2, the photoreactive analog of THI0019 remained an agonist, consistent with it binding at the /ß subunit interface and not at the ligand-binding site in the inserted ('I') domain of the L subunit. Co-administering progenitor cells with a compound such as THI0019 may provide a mechanism for enhancing stem cell therapy. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 27 |
| Volume Number | 288 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2013-07-05 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Cell Movement Drug Effects Heterocyclic Compounds With 4 Or More Rings Pharmacology Integrin Alpha4beta1 Agonists Models, Molecular Stem Cells Metabolism Antigens, CD11a Genetics Cell Adhesion Physiology Cell- And Tissue-Based Therapy Chemokine CXCL12 Chemistry Human Umbilical Vein Endothelial Cells Integrin Alpha5beta1 Jurkat Cells Cytology Vascular Cell Adhesion Molecule-1 Research Support, N.I.H., Extramural Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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