Stabilization of the activated alphaMbeta2 integrin by a small molecule inhibits leukocyte migration and recruitment

Biochemistry
Mikael BjörklundErkki Koivunen

Abstract

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.

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Citations

Jul 29, 2009·Blood·Michael StefanidakisErkki Koivunen
May 22, 2008·Journal of Inflammation·Ronald D MathisonJoseph S Davison
Aug 29, 2013·Molecular Diagnosis & Therapy·Tanja-Maria RantaJustus Reunanen
Dec 5, 2006·Journal of Molecular Biology·Holger SchmidtDieter Willbold
Jun 12, 2013·Lupus·S C FagerholmC S Lau
May 25, 2013·The Journal of Biological Chemistry·Peter VandersliceRichard A F Dixon

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