Cyclic and linear bradykinin analogues: implications for B₂ antagonist design

Abstract

Bradykinin (BK, Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) antagonists are potentially useful for treating inflammation, pain and severe trauma. To identify what chemical features might promote effective antagonism, we replaced Arg1 and Pro7 with structurally constrained and proteolytic-resistant residues, such as Bip (biphenylalanine), Dip (diphenylalanine) or 2Ind (indane amino acid). To determine which BK folding might lead to favourable interactions with receptors, the effects of cyclo(3,8) vs. cyclo(5,8) analogues were compared. The resulting BK analogues were examined for their agonistic and antagonistic activities in guinea pig ileum, rat uterus and depressor assays. The results suggest that co-planarity of the residue-7 side chain with its backbone NH is important for potent agonism as well as antagonism, and a D-directed side chain is crucial for antagonism. For residue-1 an L-orientation is important, and Dip1 may mimic a folded Arg1 side chain to elicit agonistic activities, with Bip1 mimicking an extended Arg1 side chain to elicit inhibitory activities. However, ileal and uterine receptors appear to prefer differently folded BK. For ileum, a BK conformation in which residues-3 and -8 are proximal to each other, but apart from residue-5, led to improved pA2.

Development of a synthetic cyclized peptide derived from α‐fetoprotein that prevents the growth of human breast cancer

“…Typically, shelf‐life problems have been addressed by the use of excipients (10) or by direct amino acid substitution in the peptide (11). The biphasic dose−response curve is more problematic because it is less well understood but has been addressed previously using rational design approaches (12).…”

Synthesis and biological activities of new side chain and backbone cyclic bradykinin analogues

“…Since the initial investigations of Chipens et al . (50,51), several head‐to‐tail and side chain cyclic BK analogues have been synthesized (52–57). Very recently, Biondi et al .…”

“…Because the solution conformation of a biologically active cyclic peptide is expected to be close to the bioactive conformation, we were interested in the stabilization of turn structures in BK analogues by cyclization. Since the initial investigations of Chipens et al (50,51), several head-to-tail and side chain cyclic BK analogues have been synthesized (52)(53)(54)(55)(56)(57). Very recently, Biondi et al (58) published synthesis and conformational investigations of head-to-tail cyclic bradykinin analogues with N-benzylglycine at positions 5 and 8 and Thr at position 6.…”

A cardiac tissue-specific binding agent of troponin I

“…Although normal phage libraries cannot incorporate unnatural amino acids, many conformationally constrained and unnatural residues have been incorporated into identified constructs in order to impart specific features and enhance their durability against biological degradation 12 . Phenylalanine-like analogs have been incorporated into several structures to investigate various targets 13–16 . For example, we recently demonstrated the potential of a biphenylalanine-rich peptide labeled with fluorescein isothiocyanate (FITC) as a fluorescent stain specific for viable myocardium 17 .…”