title: Potent cyclic monomeric and dimeric peptide inhibitors of VLA-4 (alpha4beta1 integrin)-mediated cell adhesion based on the Ile-Leu-Asp-Val tetrapeptide.
abstract: Potent monomeric and dimeric cyclic peptide very late antigen-4 (VLA-4) inhibitors have been designed based on a tetrapeptide (Ile-Leu-Asp-Val) sequence present in a 25-amino acid peptide (CS-1) reported in the literature. The peptides, synthesized by the SPPS techniques, were evaluated in the in vitro cell adhesion assays and in the in vivo inflammation models. The N- to C-terminal cyclic peptides such as cyclo(Ile-Leu-Asp-Val-NH-(CH2)2-S-(CH2)2-CO) (28) and cyclo(MeIle-Leu-Asp-Val-D-Ala-D-Ala) (31), monomeric and dimeric peptides containing piperazine (Pip) or homopiperazine (hPip) residues as linking groups, e.g. cyclo(MeIle-Leu-Asp-Val-Pip-CH2CO-NH-(CH2)2-S-CH2-CO) (49) and cyclo(MeIle-Leu-Asp-Val hPip-CH2CO-MeIle-Leu-Asp-Val-hPip-CH2CO) (58) and cyclic peptides containing an amide bond between the side chain amino group of an amino acid such as Lys and the C-terminal Val carboxyl group, e.g. Ac-cyclo(D-Lys-D-Ile-Leu-Asp-Val) (62) and beta-Ala-cyclo(D-Lys-D-Leu-Leu-Asp-Val) (68) were more potent than CS-1 in inhibiting the adhesion of the VLA-4-expressing MOLT-4 cells to fibronectin. The more potent compounds were highly selective and did not affect U937 cell adhesion to fibronectin (VLA-5), PMA-differentiated U937 cell adhesion to intercellular cell adhesion molecule- 1-expressing Chinese hamster ovary cells (LFA-1) and ADP-induced platelet aggregation (GPIIb/IIIa). A number of the more potent compounds inhibited ovalbumin-induced delayed type hypersensitivity in mice and some were 100-300 times more potent (ED50 = 0.003-0.009 mg/kg/day, s.c.) than CS-1. Two peptides, Ac-cyclo(D-Lys D-Ile-Leu-Asp-Val) (62) and cyclo(CH2CO-Ile-Leu-Asp-Val-Pip-CH2CO-Ile-Leu-Asp-Val-Pip) (55), were formulated in poly(DL-lactide-co-glycolide) depots and the release profile was investigated in vitro over a 30-day period.
authors.affiliation: Discovery Research, AstraZeneca, Mereside, Macclesfield, Cheshire, UK. anand.dutta@astrazeneca.com
authors.forename: A S
authors.initials: AS
authors.lastname: Dutta
authors.forename: M
authors.initials: M
authors.lastname: Crowther
authors.forename: J J
authors.initials: JJ
authors.lastname: Gormley
authors.forename: L
authors.initials: L
authors.lastname: Hassall
authors.forename: C F
authors.initials: CF
authors.lastname: Hayward
authors.forename: P R
authors.initials: PR
authors.lastname: Gellert
authors.forename: R S
authors.initials: RS
authors.lastname: Kittlety
authors.forename: P J
authors.initials: PJ
authors.lastname: Alcock
authors.forename: A
authors.initials: A
authors.lastname: Jamieson
authors.forename: J M
authors.initials: JM
authors.lastname: Moores
authors.forename: A
authors.initials: A
authors.lastname: Rees
authors.forename: L J
authors.initials: LJ
authors.lastname: Wood
authors.forename: C F
authors.initials: CF
authors.lastname: Reilly
authors.forename: D
authors.initials: D
authors.lastname: Haworth
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002448:Cell Adhesion / Q000187:drug effects*; D002460:Cell Line; D006224:Cricetinae; D003692:Delayed-Action Preparations; D019281:Dimerization; D004355:Drug Stability; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000517:prevention & control; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors*; D019344:Lactic Acid; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors*; D020298:U937 Cells
chemical_list: D003692:Delayed-Action Preparations; D039041:Integrin alpha4beta1; D016023:Integrins; D010456:Peptides, Cyclic; D011108:Polymers; D016201:Receptors, Lymphocyte Homing; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D010047:Ovalbumin