ISSN:
1573-3904
Keywords:
Integrins
;
Fibronectin
;
Vascular cell-adhesion molecule-1
;
VCAM-1
;
Pseudopeptide
;
Peptidomimetic
;
Anti-inflammatory agents
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Summary During an inflammatory response, leukocytes adhere to the blood-vessel wall and to underlying extracellular matrix-protein fibronectin via noncovalent interaction through two distinct cell-surface integrins, α5β1 and α4β1. An Arg-Gly-Asp tripeptide in the cell-binding domain of fibronectin has been demonstrated to be the major site that mediates cell attachment. Our group has previously disclosed Arg-Gly-Asp- and Arg-Cys-Asp-containing cyclic peptide cell-adhesion inhibitors, which are potentially useful as anti-inflammatory agents, particularly in the treatment of asthma and rheumatoid arthritis. Subsequently, we have incorporated a β-turn dipeptide mimic and a suitably protected Arg-Gly thiomethylene dipeptide surrogate into our lead peptides by solid-phase synthesis. The preparation of the surrogates, and the structure-activity studies of the surrogate-containing peptides are described in this paper. Complete loss of cell-adhesion inhibition activity was observed in the case of incorporation of the conformationally constrained β-turn dipeptide into a cyclic Arg-Cys-Asp peptide inhibitor. Incorporation of an Arg-Gly thiomethylene dipeptide surrogate into cyclic Arg-Gly-Asp and Arg-Cys-Asp cyclic disulfide peptide inhibitors was tolerated, resulting in cyclic pseudopeptide cell-adhesion inhibitors lacking the Arg-Gly peptide amide bond.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00131084
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