科研之友
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摘要
The alpha(4) integrins mediate leukocyte adhesion to specific counter-receptors, including vascular cell adhesion molecule-1 (VCAM-1), the fibronectin splice variant containing connecting segment 1 (CS1), and mucosal addressin cell adhesion molecule-1. A series of cyclized peptides based on the LDV sequence of CS1 were synthesized and assayed for inhibition of alpha(4) integrin binding. The most potent peptide, C*WLDVC* (where * indicates disulfide-linked residues), inhibited alpha(4) beta(1)-dependent binding of lymphocytes to VCAM-1. and CS1 with half-maximal inhibition achieved at 1 to 3 mu M of peptide. The peptide proved more potent when the lymphocytes were activated with 1 mM MnCl2; half-maximal inhibition was reached at 0.4 and 0.05 mu M for VCAM-1 and CS1, respectively. This represents a 100- to 800-fold increase in potency over a linear CS1 peptide in these same assays. C*WLDVC* also inhibited alpha(4) beta(7)-dependent lymphocyte binding to the ligands mucosal addressin cell adhesion molecule-1, VCAM-1 and CS1. Immunoprecipitation of radiolabeled integrin indicated that the peptide could bind alpha(4) beta(1) and alpha(4) beta(7) directly and elute alpha(4) beta(1) from a CS1-conjugated agarose resin. The peptide showed selectivity for alpha(4) integrins in that it effectively inhibited alpha(4) beta(1)-dependent, but not alpha(5) beta(1)-dependent, binding of cells to intact fibronectin. Due to its small size and potency, C*WLDVC* may serve as a useful tool for the study of alpha(4) integrin biology and the development of small molecule therapeutics.
- 出版日期1997-2-15
