British Journal of Pharmacology 1999-04-01

Anti-inflammatory activity of c(ILDV-NH(CH2)5CO), a novel, selective, cyclic peptide inhibitor of VLA-4-mediated cell adhesion.

D Haworth, A Rees, P J Alcock, L J Wood, A S Dutta, J J Gormley, H B Jones, A Jamieson, C F Reilly

Index: Br. J. Pharmacol. 126(8) , 1751-60, (1999)

Full Text: HTML

Abstract

1. Small, N- to C-terminal cyclized peptides containing the leucyl-aspartyl-valine (LDV) motif from fibronectin connecting segment-1 (CS-1) have been investigated for their effects on the adhesion of human T-lymphoblastic leukaemia cells (MOLT-4) to human plasma fibronectin in vitro mediated by the integrin Very Late Antigen (VLA)-4 (alpha4beta1, CD49d/CD29). 2. Cyclo(-isoleucyl-leucyl-aspartyl-valyl-aminohexanoyl-) (c(ILDV-NH(CH2)5CO)) was approximately 5 fold more potent (IC50 3.6+/-0.44 microM) than the 25-amino acid linear CS-1 peptide. Cyclic peptides containing two more or one less methylene groups had similar potency to c(ILDV-NH(CH2)5CO) while a compound containing three less methylene groups, c(ILDV-NH(CH2)2CO), was inactive at 100 microM. 3. c(ILDV-NH(CH2)5CO) had little effect on cell adhesion mediated by two other integrins, VLA-5 (alpha5,beta1, CD49e/CD29) (K562 cell adhesion to fibronectin) or Leukocyte Function Associated molecule-1 (LFA-1, alphabeta2, CD11a/CD18) (U937 cell adhesion to Chinese hamster ovary cells transfected with intercellular adhesion molecule-1) at concentrations up to 300 microM. 4. c(ILDV-NH(CH2)5CO) inhibited ovalbumin delayed-type hypersensitivity or oxazolone contact hypersensitivity in Balb/c mice when dosed continuously from subcutaneous osmotic mini-pumps (0.1-10 mg kg(-1) day(-1)). Maximum inhibition (approximately 40%) was similar to that caused by the monoclonal antibody PS/2 (7.5 mg kg(-1) i.v.) directed against the alpha4 integrin subunit. 5. c(ILDV-NH(CH2)5CO) also inhibited oxazolone contact hypersensitivity when dosed intravenously 20 h after oxazolone challenge (1-10 mg kg(-1)). Ear swelling was reduced at 3 h and 4 h but not at 1 h and 2 h post-dose (10 mg kg(-1)). 6. Small molecule VLA-4 inhibitors derived from c(ILDV-NH(CH2)5CO) may be useful as anti-inflammatory agents.


Related Compounds

Related Articles:

Repetitive postprandial hypertriglyceridemia induces monocyte adhesion to aortic endothelial cells in Goto-Kakizaki rats.

2008-05-01

[Endocr. J. 55(2) , 373-9, (2008)]

Fibronectin-alpha4beta1 integrin interactions modulate p42/44 MAPK phosphorylation in steatotic liver cold ischemia-reperfusion injury.

2005-01-01

[Transplant. Proc. 37(1) , 432-4, (2005)]

Repetitive fluctuations in blood glucose enhance monocyte adhesion to the endothelium of rat thoracic aorta.

2006-10-01

[Arterioscler. Thromb. Vasc. Biol. 26(10) , 2275-80, (2006)]

alpha4 integrin in islet allograft rejection.

2001-06-15

[Transplantation 71(11) , 1549-55, (2001)]

T lymphocyte adhesion mechanisms within inflamed human kidney: studies with a Stamper-Woodruff assay.

1999-02-01

[Am. J. Pathol. 154(2) , 503-14, (1999)]

More Articles...