TY - JOUR
AU - Haworth, Duncan
AB - 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 β‐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. Copyright © 2000 European Peptide Society and John Wiley & Sons, Ltd.
TI - Potent Cyclic Monomeric and Dimeric Peptide Inhibitors of VLA‐4 (α4β1 Integrin)‐Mediated Cell Adhesion Based on the Ile‐Leu‐Asp‐Val Tetrapeptide
JF - Journal of Peptide Science
DO - 10.1002/1099-1387(200007)6:7<321::AID-PSC259>3.0.CO;2-A
DA - 2000-01-01
UR - https://www.deepdyve.com/lp/wiley/potent-cyclic-monomeric-and-dimeric-peptide-inhibitors-of-vla-4-4-1-2NLPFh7dkr
SP - 321
EP - 341
VL - 6
IS - 7
DP - DeepDyve
ER -