Premium
Potent cyclic peptide inhibitors of VLA‐4 (α 4 β 1 integrin)‐mediated cell adhesion. Discovery of compounds like cyclo(MePhe‐Leu‐Asp‐Val‐ d ‐Arg‐ d ‐Arg) (ZD7349) compatible with depot formulation
Author(s) -
Dutta Anand S.,
Gormley James J.,
Coath Matthew,
Hassall Lorraine,
Hayward Christopher F.,
Gellert Paul R.,
Kittlety Rod S.,
Alcock Peter J.,
Ferguson Roger,
Halterman Tracy,
Jamieson Alec,
Moors Jackie A.,
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(200008)6:8<398::aid-psc270>3.0.co;2-1
Subject(s) - chemistry , cyclic peptide , peptide , chinese hamster ovary cell , cell adhesion , stereochemistry , biochemistry , cell , receptor
Additional structure–activity relationship studies on potent cyclic peptide inhibitors of very late antigen‐4 (VLA‐4) are reported. The new N ‐ to C ‐terminal cyclic hexa‐, hepta‐ and octapeptide inhibitors like cyclo(MeIle/MePhe‐Leu‐Asp‐Val‐X) (X=2–4 amino acids containing hydrophobic and/or basic side chains) were synthesized using solid phase peptide synthesis methods. The peptides were evaluated in in vitro cell adhesion assays and in in vivo inflammation models. Many of the peptides like cyclo(MePhe‐Leu‐Asp‐Val‐ d ‐Arg‐ d ‐Arg) (ZD7349) ( 17 ), cyclo(MeIle‐Leu‐Asp‐Val‐ d ‐Arg‐ d ‐Arg‐ d ‐Phe) ( 20 ), cyclo(MeIle‐Leu‐Asp‐Val‐ d ‐Arg‐ d ‐Arg‐MePhe) ( 21 ) and cyclo(MePhe‐Leu‐Asp‐Val‐ d ‐Arg‐ d ‐Arg‐ d ‐Ala‐ d ‐Ala) ( 23 ) were potent inhibitors of VLA‐4‐mediated cell adhesion and inhibited ovalbumin‐induced delayed type hypersensitivity (DTH) response in mice. The more potent compounds were highly selective and did not affect U937 cell adhesion to fibronectin (VLA‐5), phorbolmyristate acetate or PMA‐differentiated U937 cell adhesion to intercellular cell adhesion molecule‐1 (ICAM‐1)‐expressing Chinese hamster ovary cells (LFA‐1) and adenosine diphosphate (ADP)‐induced platelet aggregation (GPIIb/IIIa). In contrast to the inhibitors like Ac‐cyclo( d ‐Lys‐ d ‐Ile‐Leu‐Asp‐Val) and cyclo(CH 2 CO‐Ile‐Leu‐Asp‐Val‐Pip‐CH 2 CO‐Ile‐Leu‐Asp‐Val‐Pip) described earlier, the new compounds were much more compatible with the depot formulations based on poly( dl ‐lactide‐co‐glycolide) polymers. The hexapeptide cyclo(MePhe‐Leu‐Asp‐Val‐ d ‐Arg‐ d ‐Arg) (ZD7349) ( 17 ) inhibited MOLT‐4 cell adhesion to fibronectin and vascular cell adhesion molecule‐1 (VCAM‐1) with IC 50 values of 260 and 330 n m , respectively, and did not show any significant effect against other integrins (IC 50 >300 μ m ). ZD7349 inhibited ovalbumin‐induced DTH response in mice when administered continuously using a mini‐pump (ED 50 0.01 mg/kg/day) or when given as an s.c. or i.v. bolus injection at a dose of 1–10 mg/kg. ZD7349 was also active in type II collagen‐induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE) tests at a dose of 3–10 mg/kg. The peptide was released from some formulations over a period of 10–20 days. ZD7349 is currently undergoing pre‐clinical investigation. Copyright © 2000 European Peptide Society and John Wiley & Sons, Ltd.