An NMR conformational analysis of cyclic bradykinin mimics. Evidence for a beta-turn.
A detailed NMR study is carried out in acetonitrile/water solutions on three novel cyclic bradykinin antagonist analogues, BKM-824, BKM-870, and BKM-872, to examine their solution structures, and to correlate the structures with bradykinin antagonist and anti-cancer activities. The solution structures of the cyclic peptides are correlated with the structural data for known linear bradykinin antagonists. The sequences are: BKM-824 c[Ava-Ig1-Ser-DF5F-Oic-Arg] where Ava is 5-aminovaleric acid, Ig1 is alpha-(2-indanyl)glycine, F5F is pentafluorophenylalanine, and Oic is (2S,3aS,7aS)-octahydroindole-2-carboxylic acid; BKM-870; c[DArg-Arg-Add-DF5F-Oic-Arg] where Add is 12-aminododecanoic acid; and BKM-872; c[DArg-Arg-Eac-Ser-DF5F-Oic-Arg] where Eac is 6-aminocaproic acid. BKM-824 was the only peptide within this series that possessed a discernable solution structure. The NMR data indicate the presence of a type I beta-turn between residues F5F4 and Ava1, a C-terminal-like end. Molecular dynamics calculations show that a type I beta-turn from DF5F4 to Ava1 does exist although the turn was somewhat distorted. This result differs from the structures seen in linear bradykinin antagonists, which usually possess a type II'beta-turn at the C-terminal end and the presence of a defined turn is correlated with bradykinin antagonist activity. There is no solution structure for BKM-870 and BKM-872 but a correlation between the primary sequence Arg(terminal)-DArg1-Arg2-long chain aliphatic amino acid and anti-cancer activity is evident.
Miskolzie
M
M
Department of Chemistry, University of Alberta, Edmonton, Canada.
Yamamoto
H
H
York
E J
EJ
Stewart
J M
JM
Kotovych
G
G
D000595:Amino Acid Sequence; D001920:Bradykinin / Q000037:antagonists & inhibitors / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D013053:Spectrophotometry; D005466:Fluorocarbons
C417045:BKM 870; C417046:BKM 872; D001920:Bradykinin; D010455:Peptides; D010456:Peptides, Cyclic; D005466:Fluorocarbons