Dm. Nowlin et al., A NOVEL CYCLIC PENTAPEPTIDE INHIBITS ALPHA-4-BETA-1 AND ALPHA-5-BETA-1 INTEGRIN-MEDIATED CELL-ADHESION, The Journal of biological chemistry, 268(27), 1993, pp. 20352-20359
Lymphocytes and monocytes initiate and modulate inflammatory and immun
e responses for host defense. This process is dependent upon extravasa
tion of leukocytes from the circulation to sites of antigenic challeng
e and is controlled, in part, by various integrins, including alpha4be
ta1 and alpha5beta1. A small cyclic pentapeptide that inhibits, in vit
ro, both alpha4beta1 and alpha5beta1 activity is described. This pepti
de, Arg-Cys-Asp-Thioproline-Cys (RCD[ThioP]C*), is cyclized by a disu
lfide bond through the cysteine residues (the asterisks denote cyclizi
ng residues). RCD(ThioP)C* inhibits alpha5beta1-mediated leukocyte ad
hesion to the 120-kDa Arg-Gly-Asp (RGD)-containing binding site of fib
ronectin. Two different adhesion activities of alpha4beta1 are also in
hibited: alpha4beta1-mediated cell adhesion to the alternatively splic
ed CS-1 site of fibronectin and the alpha4beta1-dependent binding of l
eukocytes to cytokine-activated endothelial cells. Both alpha4beta1 an
d alpha5beta1 can be purified by affinity chromatography using the imm
obilized pentapeptide. The peptide does not inhibit adhesion to other
extracellular matrix proteins including laminin and vitronectin. The s
pecificity of the RCD(ThioP)C* peptide for alpha4beta1 and alpha5beta
1 suggests potential therapeutic utility for inhibiting inflammatory d
isease.