An NMR conformational analysis of cyclic bradykinin mimics. Evidence for a beta-turn.

Abstract

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.

• Authors: M Miskolzie, H Yamamoto, E J York, J M Stewart, G Kotovych
• Journal: Journal of biomolecular structure & dynamics (J Biomol Struct Dyn) Vol. 17 Issue 6 Pg. 947-55 (Jun 2000) ISSN: 0739-1102 [Print] England
• PMID: 10949162 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BKM 824
• BKM 870
• BKM 872
• Peptides
• Peptides, Cyclic
• Bradykinin

Topics

• Amino Acid Sequence
• Bradykinin (antagonists & inhibitors, chemistry)
• Magnetic Resonance Spectroscopy
• Models, Molecular
• Molecular Sequence Data
• Peptides (chemical synthesis)
• Peptides, Cyclic (chemistry, pharmacology)
• Protein Conformation
• Protein Structure, Secondary
• Spectrophotometry