An NMR Conformational Analysis of Cyclic Bradykinin Mimics. Evidence for a β-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.

α-Hydrazino Acid Insertion Governs Peptide Organization in Solution by Local Structure Ordering

“…3D models of α-hydrazino peptides h­(1) , h­(4) , and h­(8) with single-site modifications revealed the effect of an additional sp 3 -hybridized nitrogen atom, which causes rotation of the backbone by rearranging hydrogen bond network. Ultimately, this leads to peptide structuring in the form of a γ-, β-, hydrazino-, or α-turn, which could play an important role in various biological ligand–receptor interactions, such as binding to G-protein coupled receptors ,− or integrin recognition . This observation confirms the use of this modification in the de novo design of various receptor inhibitors.…”

Systematic Study of the Synthesis of Macrocyclic Dipeptide β-Turn Mimics Possessing 8-, 9-, and 10- Membered Rings by Ring-Closing Metathesis

“…Polar in nature, these secondary structures generally occupy the surfaces of protein molecules, where they are involved in recognition and binding . β-turns have also been shown to be important for receptor affinity in biologically active peptides, such as somatostatin, MSH, bradykinin, and LHRH . Mimics of β-turns are thus desirable tools for studying the structure−activity relationships responsible for protein and peptide biology …”

Aza-β3-cyclotetrapeptides

“…β-Turns, generally located on the solvent-exposed surface of proteins, play important roles as recognition and binding sites in numerous biological events . β-Turns are also implied in the receptor affinity of Somatostatin, Bradykinin, and other biologically important peptides. , Natural CTPs also display interesting biological effects . In particular, Apicidin shows antiprotozoal activities with possible development as antimalarial agents .…”