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Chimeric strategies for the rational design of bioactive analogs of small peptide hormones
Author(s) -
Howl John,
Langel ülo,
Hawtin Stuart R.,
Valkna Andres,
Yarwood Nicola J.,
Saar Külliki,
Wheatley Mark
Publication year - 1997
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.11.7.9212082
Subject(s) - rational design , hormone , peptide , chemistry , computational biology , pharmacology , biology , biochemistry , genetics
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 B 2 , bradykinin receptor (B 2a 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 B 2 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 V 1a vasopressin receptor (V 1a VPR) and the B 2a 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 V 1a ‐selective antagonist represent the first examples of new classes of B 2 BKR and V la 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)