Potent cyclic monomeric and dimeric peptide inhibitors of VLA-4 (alpha(4)beta(1) integrin)-mediated cell adhesion based on the Ile-Leu-Asp-Val tetrapeptide

Citation
As. Dutta et al., Potent cyclic monomeric and dimeric peptide inhibitors of VLA-4 (alpha(4)beta(1) integrin)-mediated cell adhesion based on the Ile-Leu-Asp-Val tetrapeptide, J PEPT SCI, 6(7), 2000, pp. 321-341
Citations number
41
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF PEPTIDE SCIENCE
ISSN journal
10752617 → ACNP
Volume
6
Issue
7
Year of publication
2000
Pages
321 - 341
Database
ISI
SICI code
1075-2617(200007)6:7<321:PCMADP>2.0.ZU;2-I
Abstract
Potent monomeric and dimeric cyclic peptide very late antigen-4 (VLA-4) inh ibitors have been designed based on a tetrapeptide (Ile-Leu-Asp-Val) sequen ce present in a 25-amino add peptide (CS-1) reported in the literature. The peptides, synthesized by the SPPS techniques, were evaluated in the in vit ro 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 d imeric peptides containing piperazine (Pip) or homopiperazine (hPip) residu es as linking groups, e.g. cyclo(Melle-Leu-Asp-Val-Pip-CH2CO-NH-(CH2)(2)-S- CH2-CO (49) and cyclo(MeIle-Leu-Asp-Valh-Pip-CH2CO-Melle-Leu-Asp-Val-hPip-C H2CO) (58) and cyclic peptides containing an amide bond between the side ch ain amino group of an amino acid such as Lys and the C-terminal Val carboxy l group, e.g. Ac-cyclo(D-Lys-D-Ile-Leu-Asp-Val) (62) and beta-Ala-cyclo(D-L ys-o-LRu-Leu-Asp-Val) (68) were more potent than CS-1 in Inhibiting tl-le a dhesion of the VLA-4-expressing MOLT-4 cells to fibronectin. The more poten t 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 (LFR-1) an d ADP-induced platelet aggregation (GPIIb/IIIa). A number of the more poten t compounds inhibited ovalbumin-induced delayed type hypersensitivity in mi ce 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) (82) and cy clo(CH2CO-Ile-Leu-Asp-Val-Pip-CH2CO-Ile-Leu-Asp-Val-Pip) (55), were formula ted in poly(DL-lactide-co-glycolide) depots and the release profile was inv estigated in vitro over a 30-day period. Copyright (C) 2000 European Peptid e Society and John Wiley & Sons, Ltd.