Stabilization of the activated alphaMbeta2 integrin by a small molecule inhibits leukocyte migration and recruitment.
Biochemistry
; 45(9): 2862-71, 2006 Mar 07.
Article
em En
| MEDLINE
| ID: mdl-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.
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Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Tiazóis
/
Movimento Celular
/
Antígeno de Macrófago 1
/
Leucócitos
/
Anti-Inflamatórios
Limite:
Animals
Idioma:
En
Revista:
Biochemistry
Ano de publicação:
2006
Tipo de documento:
Article
País de afiliação:
Finlândia