Premium
Potent Cyclic Monomeric and Dimeric Peptide Inhibitors of VLA‐4 (α 4 β 1 Integrin)‐Mediated Cell Adhesion Based on the Ile‐Leu‐Asp‐Val Tetrapeptide
Author(s) -
Dutta Anand S.,
Crowther Mandy,
Gormley James J.,
Hassall Lorraine,
Hayward Christopher F.,
Gellert Paul R.,
Kittlety Rod S.,
Alcock Peter J.,
Jamieson Alec,
Moores Julie M.,
Rees Amanda,
Wood Linda J.,
Reilly Christopher F.,
Haworth Duncan
Publication year - 2000
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/1099-1387(200007)6:7<321::aid-psc259>3.0.co;2-a
Subject(s) - tetrapeptide , chemistry , peptide , cyclic peptide , stereochemistry , cell adhesion , amino acid , chinese hamster ovary cell , integrin , biochemistry , cell , receptor
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‐(CH 2 ) 2 ‐S‐(CH 2 ) 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‐CH 2 CO‐NH‐(CH 2 ) 2 ‐S‐CH 2 ‐CO) ( 49 ) and cyclo(MeIle‐Leu‐Asp‐Val‐hPip‐CH 2 CO‐MeIle‐Leu‐Asp‐Val‐hPip‐CH 2 CO) ( 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 (ED 50 =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(CH 2 CO‐Ile‐Leu‐Asp‐Val‐Pip‐CH 2 CO‐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.