Small molecule agonist of very late antigen-4 (VLA-4) integrin induces progenitor cell adhesion.

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 ?4?1 (also known as very late antigen-4 or VLA-4). The agonist, THI0019, was generated via two structural modifications to a previously identified ?4?1 antagonist. THI0019 greatly enhanced the adhesion of cultured cell lines and primary progenitor cells to ?4?1 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 ?/? 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 ?4?7 as well as ?5?1 and ?L?2. When cross-linked to ?L?2, the photoreactive analog of THI0019 remained an agonist, consistent with it binding at the ?/? 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.

SUBMITTER: Vanderslice P 

PROVIDER: S-EPMC3707645 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature