Stabilization of the activated alphaMbeta2 integrin by a small molecule inhibits leukocyte migration and recruitment.
Integrins are potential targets for the development of antiinflammatory agents. Here we develop a novel high-throughput assay by allowing a chemical library to compete with phage display peptide binding and identify a novel small-molecule ligand to the leukocyte-specific alpha(M)beta(2) integrin. The identified thioxothiazolidine-containing compound, IMB-10, had an unexpected activity in that it stabilized binding of alpha(M)beta(2) to its endogenous ligands proMMP-9 and fibrinogen. Single amino acid substitutions in the activity-regulating C-terminal helix and the underlying region in the ligand-binding I domain of the integrin suppressed the effect of IMB-10. A computational model indicated that IMB-10 occupies a distinct cavity present only in the activated form of the integrin I domain. IMB-10 inhibited alpha(M)beta(2)-dependent migration in vitro and inflammation-induced neutrophil emigration in vivo. Stabilization of integrin-mediated adhesion by a small molecule is a novel means to inhibit cell migration and may have a utility in treatment of inflammatory diseases involving leukocyte recruitment.
Björklund
Mikael
M
Department of Biological and Environmental Sciences, University of Helsinki, Helsinki FI-00014, Finland.
Aitio
Olli
O
Stefanidakis
Michael
M
Suojanen
Juho
J
Salo
Tuula
T
Sorsa
Timo
T
Koivunen
Erkki
E
D000595:Amino Acid Sequence; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects*; D005260:Female; D007962:Leukocytes / Q000378:metabolism*; D008024:Ligands; D016177:Macrophage-1 Antigen / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019151:Peptide Library; D017434:Protein Structure, Tertiary / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000893:Anti-Inflammatory Agents; C509839:IMB 10; D008024:Ligands; D016177:Macrophage-1 Antigen; D019151:Peptide Library; D011993:Recombinant Fusion Proteins; D013844:Thiazoles