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.

journal_name

Peptides

journal_title

Peptides

authors

Brauns O,Brauns S,Jenke M,Zimmermann B,Dautzenberg FM

doi

10.1016/s0196-9781(02)00139-0

subject

Has Abstract

pub_date

2002-10-01 00:00:00

pages

1817-27

issue

10

eissn

0196-9781

issn

1873-5169

pii

S0196978102001390

journal_volume

23

pub_type

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