A Small Molecule Agonist of an Integrin , ! L " 2 * □

The binding of integrin !L"2 to its ligand intercellular adhesion molecule-1 is required for immune responses and leukocyte trafficking. Small molecule antagonists of !L"2 are under intense investigation as potential anti-inflammatory drugs. We describe for the first time a small molecule integrin agonist. A previously described !/" I allosteric inhibitor, compound 4, functions as an agonist of !L"2 in Ca2# and Mg2# and as an antagonist in Mn2#. We have characterized the mechanism of activation and its competitive and noncompetitive inhibition by different compounds. Although it stimulates ligand binding, compound 4 nonetheless inhibits lymphocyte transendothelial migration. Agonism by compound 4 results in accumulation of !L"2 in the uropod, extreme uropod elongation, and defective de-adhesion. Small molecule integrin agonists open up novel therapeutic possibilities.