Anti‐inflammatory activity of c(ILDV‐NH(CH 2 ) 5 CO), a novel, selective, cyclic peptide inhibitor of VLA‐4‐mediated cell adhesion

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 (α 4 β 1 , CD49d/CD29). Cyclo(‐isoleucyl‐leucyl‐aspartyl‐valyl‐aminohexanoyl‐) (c(ILDV‐NH(CH 2 ) 5 CO)) was approximately 5 fold more potent (IC 50 3.6±0.44 μ M ) 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(CH 2 ) 5 CO) while a compound containing three less methylene groups, c(ILDV‐NH(CH 2 ) 2 CO), was inactive at 100 μ M . c(ILDV‐NH(CH 2 ) 5 CO) had little effect on cell adhesion mediated by two other integrins, VLA‐5 (α 5 ,β 1 , CD49e/CD29) (K562 cell adhesion to fibronectin) or Leukocyte Function Associated molecule‐1 (LFA‐1, α L β 2 , CD11a/CD18) (U937 cell adhesion to Chinese hamster ovary cells transfected with intercellular adhesion molecule‐1) at concentrations up to 300 μ M . c(ILDV‐NH(CH 2 ) 5 CO) 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 α 4 integrin subunit. c(ILDV‐NH(CH 2 ) 5 CO) 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(CH 2 ) 5 CO) may be useful as anti‐inflammatory agents.British Journal of Pharmacology (1999) 126 , 1751–1760; doi: 10.1038/sj.bjp.0702511