Stereoisomerism and biological activity of the selective and superactive α(v)β3 integrin inhibitor cyclo(-RGDfV-) and its retro-inverso peptide

J. Wermuth, S. L. Goodman, A. Jonczyk, H. Kessler

Publikation: Beitrag in FachzeitschriftArtikelBegutachtung

138 Zitate (Scopus)

Abstract

The cyclic pentapeptide cyclo(-Arg-Gly-Asp-D-Phe-Val-) is a highly potent and selective inhibitor for the α(v)β3 integrin and is a prospective anticancer drug by acting to inhibit angiogenesis and by inducing apoptosis in vascular cells. The cyclic retro-inverso peptides as well as the inverso and the cyclic retro peptide analogs of the four cyclic Arg-Gly-Asp-Phe-Val peptides with one amino acid in the D configuration and the corresponding all-L peptide have been synthesized. The inhibitory activities of 18 compounds have been tested on the isolated integrin α(IIb)β3 and α(v)β3 receptors. The conformations of the cyclic retro-inverso pentapeptides were investigated by NMR spectroscopy using NOEs, ROEs, and coupling constants and were determined by distance geometry (DG) calculations. The structures were compared to their parent analogs, and the relationship between their conformation and the biological activity is discussed. Due to the reversal of the peptide bonds in the retro-inverso peptides, the hydrogen bond pattern is shifted and the spatial structure differs from its parent compound structure. These conformational changes result in a dramatic decrease of activity in comparison to the high-active parent peptides. On the other hand the retro-inverso peptide analog of the poorly active parent peptide cyclo(-D-Arg-Gly-Asp-Phe-Val-) was found to be highly active and selective for the α(v)β3 receptor. Furthermore, the almost perfect similarity of the side chain orientation between the highly active peptide cyclo(-Arg-Gly-Asp-D-Phe-Val-) and the inactive retro-inverso peptide cyclo(-Val-D-Phe-D-Asp-Gly-D-Arg-) indicates a distinct interaction of at least one peptide bond of the backbone with the α(v)β3 receptor.

OriginalspracheEnglisch
Seiten (von - bis)1328-1335
Seitenumfang8
FachzeitschriftJournal of the American Chemical Society
Jahrgang119
Ausgabenummer6
DOIs
PublikationsstatusVeröffentlicht - 12 Feb. 1997

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