Small molecule agonist of very late antigen-4 (VLA-4) integrin induces progenitor cell adhesion
Author & Article Information
Authors: Peter Vanderslice (pvanderslice@texasheart.org), Ronald J. Biediger, Darren G. Woodside, Wells S. Brown, Sayadeth Khounlo, Navin D. Warier, C. William Gundlach, IV, Amy R. Caivano, William G. Bornmann, David S. Maxwell, Bradley W. McIntyre, James T. Willerson, Richard A.F. Dixon
Affiliations: From the Department of Molecular Cardiology, Texas Heart Institute at St. Luke's Episcopal Hospital, The Departments of Immunology, Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030. This work was supported, in whole or in part, by National Institutes of Health Grant 2 T32-CA-09598-21 (to W. S. B.). P. V., R. J. B., and C. W. G. are named on a patent application that was submitted by the Texas Heart Institute. This article contains supplemental Movies 1–4.
Publication History: Received April 22, 2013; Revised May 22, 2013; Published online May 23, 2013
DOI: 10.1074/jbc.M113.479634Also available on ScienceDirect
Copyright: © 2013 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.
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 α4β1 (also known as very late antigen-4 or VLA-4). The agonist, THI0019, was generated via two structural modifications to a previously identified α4β1 antagonist. THI0019 greatly enhanced the adhesion of cultured cell lines and primary progenitor cells to α4β1 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-1α. Molecular modeling predicted that the compound binds at the α/β 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 α4β7 as well as α5β1 and αLβ2. When cross-linked to αLβ2, the photoreactive analog of THI0019 remained an agonist, consistent with it binding at the α/β subunit interface and not at the ligand-binding site in the inserted (“I”) domain of the αL subunit. Co-administering progenitor cells with a compound such as THI0019 may provide a mechanism for enhancing stem cell therapy.
See the original article here | Journal of Biological Chemistry