Chimeric strategies for the rational design of bioactive analogs of small peptide hormones

• Published in: The FASEB journal 1997-06, Vol.11 (7), p.582-591
• Main Authors: Howl, John, Langel, ülo, Hawtin, Stuart R., Valkna, Andres, Yarwood, Nicola J., Saar, Külliki, Wheatley, Mark
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; antagonist; Arginine Vasopressin - chemical synthesis; Arginine Vasopressin - pharmacology; bradykinin; Bradykinin - chemical synthesis; Bradykinin - pharmacology; Cattle; Cell Line; Cell Membrane - metabolism; Dimerization; Drug Design; galanin; GTP-Binding Proteins - metabolism; Ligands; mastoparan; Molecular Sequence Data; Peptides - chemical synthesis; Peptides - pharmacology; Rats; Receptors, Bradykinin - metabolism; Receptors, Vasopressin - metabolism; Recombinant Fusion Proteins - chemical synthesis; Recombinant Fusion Proteins - pharmacology; Structure-Activity Relationship; vasopressin
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.11.7.9212082

The aim of this study was to evaluate a variety of synthetic strategies pertinent to the development of chimeric analogs of the structurally divergent nonapeptide hormones arginine vasopressin (AVP) and bradykinin (BK). Single‐chain peptides combining AVP and BK directly, AVP(l–9)‐BK(l–9) or via a flexible aminohexanoic acid (εAhx) linker, AVP(1–9)‐εAhx‐BK(1–9), bind with relatively high affinity to the bovine kidney medulla B2, bradykinin receptor (B2a BKR). Significantly, ammo‐terminal extended chimeric analogs of BK, including AVP(1–9)‐BK(1–9) and galanin(1–13)‐BK(1–9), are functional B2 BKR agonists. These findings illustrate that chimeric peptides can activate G‐protein‐coupled receptors (GPCRs) in a manner analogous to that of endogenous monomelic agonists. Further development, combining the sequences of receptor subtype‐selective antagonists, produced high‐affinity chimeric antagonists of the V1a vasopressin receptor (V1a VPR) and the B2a BKR. We also determined the pharmacological characteristics of high‐affinity chimeric hormone analogs derivatized with the membrane targeting function of mastoparan. Homodimers of an amino‐terminal extended BK analog and a V1a‐selective antagonist represent the first examples of new classes of B2 BKR and Vla VPR antagonists, respectively. These findings are discussed in relation to the GPCR binding site for small peptides and the development of novel biological probes and therapeutic agents.—Howl, J., Langel, Ü, Hawtin, S. R., Valkna, A., Yarwood, N. J., Saar, K., Wheatley, M. Chimeric strategies for the rational design of bioactive analogs of small peptide hormones. FASEB J. 11, 582–590 (1997)