M. Coles et al., A CONFORMATIONAL STUDY BY H-1-NMR OF A CYCLIC PENTAPEPTIDE ANTAGONISTOF ENDOTHELIN, Journal of medicinal chemistry, 36(18), 1993, pp. 2658-2665
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 an
nealing calculations based on NOE constraints. Additional information
used in the structure determination included coupling constants and ch
emical-shift measurements as a function of temperature. The chemical s
hifts of two of the NH protons (D-Glu and D-Ile) exhibit low sensitivi
ty to changes in temperature, indicating their involvement in hydrogen
-bonded interactions. The main features of interest in the solution co
nformation include the presence of both a type-II beta-turn and an inv
erse gamma-turn, with central hydrogen bonds between HN of D-Glu1 and
the C=O Of D-allo-Ile3 and between H(N) 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 rec
ently derived structures for BQ123, cyclo(D-Asp-L-Pro-D-Val-L-LeU-D-Tr
p), another highly potent endothelin antagonist. The backbone conforma
tions of the two cyclic peptides are found to be similar. Comparisons
with literature structure-activity data suggest that these peptides ma
y mimic structural features of the C-terminal tail of the endothelins.