| Autor: |
Haworth, Duncan, Rees, Amanda, Alcock, Peter J, Wood, Linda J, Dutta, Anand S, Gormley, James J, Jones, Huw B, Jamieson, Alec, Reilly, Christopher F |
| Zdroj: |
British Journal of Pharmacology; April 1999, Vol. 126 Issue: 8 p1751-1760, 10p |
| Abstrakt: |
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 vitromediated by the integrin Very Late Antigen (VLA)‐4 (α4β1, CD49d/CD29).Cyclo(‐isoleucyl‐leucyl‐aspartyl‐valyl‐aminohexanoyl‐) (c(ILDV‐NH(CH2)5CO)) was approximately 5 fold more potent (IC503.6±0.44 μM) 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 μM.c(ILDV‐NH(CH2)5CO) had little effect on cell adhesion mediated by two other integrins, VLA‐5 (α5,β1, CD49e/CD29) (K562 cell adhesion to fibronectin) or Leukocyte Function Associated molecule‐1 (LFA‐1, αLβ2, CD11a/CD18) (U937 cell adhesion to Chinese hamster ovary cells transfected with intercellular adhesion molecule‐1) at concentrations up to 300 μM.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−1day−1). Maximum inhibition (approximately 40%) was similar to that caused by the monoclonal antibody PS/2 (7.5 mg kg−1i.v.) directed against the α4integrin subunit.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).Small molecule VLA‐4 inhibitors derived from c(ILDV‐NH(CH2)5CO) may be useful as anti‐inflammatory agents. |
| Databáze: |
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