title: Secondary structure of antisauvagine analogues is important for CRF receptor antagonism: development of antagonists with increased potency and receptor selectivity.
abstract: Antisauvagine-30 (aSVG) is the only high-affinity antagonist for the corticotropin-releasing factor (CRF) type 2 (CRF(2)) receptor. A structure-activity relationship study was performed to pinpoint residues conferring aSVG's selectivity. The aSVG-analogues being N-terminally extended by one or two residues or containing the Ala(22)Arg(23)Ala(24) (ARA-motif) of CRF, were synthesized. Additionally, a lactam bridge between positions 29 and 32 was introduced. The modified peptides were analyzed for alpha-helicity properties, binding affinities and antagonistic potencies at the rat CRF(1) and mouse CRF(2B) receptors. While N-terminal prolongation and replacement of D-Phe(11) by Tyr(11) increased the affinity for the CRF(2) receptor, the introduction of the ARA motif resulted in a loss of CRF(2) receptor selectivity. These data show that aSVG(10-40) analogues are more potent CRF(2) receptor antagonists than aSVG(11-40) peptides, while introduction of the ARA-motif or a cyclic constraint between residues 29 and 32 favors binding to the CRF(1) receptor.
authors.affiliation: Department of Molecular Neuroendocrinology, Max Planck Institute of Experimental Medicine, Hermann Rein Str. 3, 37075 Goettingen, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Brauns
authors.forename: Simone
authors.initials: S
authors.lastname: Brauns
authors.forename: Marc
authors.initials: M
authors.lastname: Jenke
authors.forename: Bodo
authors.initials: B
authors.lastname: Zimmermann
authors.forename: Frank M
authors.initials: FM
authors.lastname: Dautzenberg
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D002942:Circular Dichroism; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D007769:Lactams / Q000737:chemistry; D051379:Mice; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D007769:Lactams; D010446:Peptide Fragments; D018019:Receptors, Corticotropin-Releasing Hormone; C116607:antisauvagine 30; D000242:Cyclic AMP