A conformational study by 1H NMR of a cyclic pentapeptide antagonist of endothelin.
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.
Coles
M
M
School of Pharmaceutical Chemistry, Victorian College of Pharmacy, Parkville, Australia.
Sowemimo
V
V
Scanlon
D
D
Munro
S L
SL
Craik
D J
DJ
D000595:Amino Acid Sequence; D016232:Endothelins / Q000037:antagonists & inhibitors*; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D012996:Solutions; D013329:Structure-Activity Relationship
D016232:Endothelins; D010456:Peptides, Cyclic; D012996:Solutions; C069764:cyclo(glutamyl-alanyl-isoleucyl-leucyl-tryptophyl)