MEDI 21 |
| The integrin CD11b/CD18 is the predominant Beta2 (β2) integrin receptor in leukocytes and plays a central role in mediating pro-inflammatory functions of these cells. In vivo, the binding of integrin CD11b/CD18 to its physiologic ligands is carefully controlled and this integrin is expressed in a low affinity (inactive) conformation on the surface of circulating cells. Additionally, the interaction between CD11b/CD18 integrin and its physiologic ligands is of low affinity, which poses a challenge in the development of cell-based adhesion assays for the high throughput screening (HTS) environment. We recently developed a simple, novel cell-based HTS assay for screening a library of small molecules against CD11b/CD18. Using this assay, we screened >20,000 compounds and identified several unique small molecule agonists, some of which showed good selectivity for CD11b/CD18 over a highly related integrin CD11a/CD18 in secondary assays. Here, we will describe the use these agonists as in vivo chemical biology probes in mouse and zebrafish models of human disease for selectively modulating the function of integrin CD11b/CD18. We will also discuss the insights gained in using such small molecules for functional modulation of cell surface receptors in vivo as well as the challenges that lie ahead. |
|
General Oral Session
1:30 PM-4:50 PM, Sunday, August 19, 2007 BCEC -- 210A, Oral
Division of Medicinal Chemistry |