Journal of Medicinal Chemistry 1993-09-03

A conformational study by 1H NMR of a cyclic pentapeptide antagonist of endothelin.

M Coles, V Sowemimo, D Scanlon, S L Munro, D J Craik

Index: J. Med. Chem. 36(18) , 2658-65, (1993)

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Abstract

The selective endothelin antagonist cyclo(D-Glu-L-Ala-D-allo-Ile-L-Leu-D-Trp, BE18257B) has been synthesized via solid-phase methods and its solution conformation determined by NMR spectroscopy and simulated annealing calculations based on NOE constraints. Additional information used in the structure determination included coupling constants and chemical-shift measurements as a function of temperature. The chemical shifts of two of the NH protons (D-Glu and D-Ile) exhibit low sensitivity to changes in temperature, indicating their involvement in hydrogen-bonded interactions. The main features of interest in the solution conformation include the presence of both a type-II beta-turn and an inverse gamma-turn, with central hydrogen bonds between HN of D-Glu1 and the C = O of D-allo-Ile3 and between HN of D-allo-Ile3 and the C = O of D-Glu1. The correlation of this solution conformation to the peptide's biological activity is discussed. The data are also compared with recently derived structures for BQ123, cyclo(D-Asp-L-Pro-D-Val-L-Leu-D-Trp), another highly potent endothelin antagonist. The backbone conformations of the two cyclic peptides are found to be similar. Comparisons with literature structure-activity data suggest that these peptides may mimic structural features of the C-terminal tail of the endothelins.