Inhibition of β2 integrin-mediated leukocyte cell adhesion by leucine-leucine-glycine motif-containing peptides

Many integrins mediate cell attachment to the extracellular matrix by recognizing short tripeptide sequences such as arginine-glycine-aspartic acid and leucine-aspartate-valine. Using phage display, we have now found that the leukocyte-specific beta (7) integrins bind sequences containing a leucine-leucine-glycine (LLG) tripeptide motif. An LLG motif is present on intercellular adhesion molecule (ICAM)-1, the major beta (2) integrin Ligand, but also on several matrix proteins, including von Willebrand factor. We developed a novel beta (2) integrin antagonist peptide CPCFLLGCC (called LLG-C4,), the structure of which was determined by nuclear magnetic resonance. The LLG-C4 peptide inhibited leukocyte adhesion to ICAM-1. and, interestingly, also to von Willebrand factor. When immobilized on plastic, the LLG-C4 sequence supported the beta (2) integrin-mediated leukocyte adhesion, but not beta (1) or beta (3) integrin-mediated cell adhesion. These results suggest that LLG sequences exposed on ICAM-1 and on von Willebrand factor at sites: of vascular injury play a role in the binding of leukocytes. and LLG-C4 and peptidomimetics derived from it could provide a therapeutic approach to inflammatory reactions.