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Stabilization of the Activated alphaMbeta2 Integrin by a Small Molecule Inhibits Leukocyte Migration and Recruitment

Stabilization of the Activated alphaMbeta2 Integrin by a Small Molecule Inhibits Leukocyte Migration and Recruitment

Mikael Björklund, Olli Aitio, Michael Stefanidakis, Juho Suojanen, Tuula Salo, Timo Sorsa, Erkki Koivunen

Biochemistry. 2006 Mar 7;45(9):2862-71.

PMID: 16503641

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP307525402	IMB-10		307525-40-2	Price

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