2014年4月10日星期四

Astressin-B peptide

Astressin-B peptide

We present evidence that members of the corticotropin releasing factor (CRF) family assume distinct structures when interacting with the CRF1 and CRF2 receptors. Predictive methods, physicochemical measurements, and structure−activity relationship studies have suggested that CRF, its family members, and competitive antagonists such as astressin {cyclo(30−33)[DPhe12,Nle21,Glu30,Lys33,Nle38]hCRF(12-41)} assume an α-helical conformation when interacting with their receptors. We had shown that α-helical CRF(9-41) and sauvagine showed some selectivity for CRF receptors other than that responsible for ACTH secretion1and later for CRF2.2 More recently, we suggested the possibility of a helix-turn-helix motif around a turn encompassing residues 30−333 that would confer high affinity for both CRF1and CRF22,4 in agonists and antagonists of all members of the CRF family.3 On the other hand, the substitutions that conferred ca. 100-fold CRF2 selectivity to the antagonist antisauvagine-30 {[DPhe11,His12]sauvagine(11-40)} did not confer such property to the corresponding N-terminally extended agonists. We find here that a Glu32-Lys35 side chain to side chain covalent lactam constraint in hCRF and the corresponding Glu31-Lys34 side chain to side chain covalent lactam constraint in sauvagine yield potent ligands that are selective for CRF2. Additionally, we introduced deletions and substitutions known to increase duration of action to yield antagonists such as cyclo(31−34)[DPhe11,His12,CαMeLeu13,39,Nle17,Glu31,Lys34]Ac-sauvagine(8-40) (astressin2-B) with CRF2selectivities greater than 100-fold. CRF receptor autoradiography was performed in rat tissue known to express CRF2 and CRF1 in order to confirm that astressin2-B could indeed bind to established CRF2 but not CRF1 receptor-expressing tissues. Extended duration of action of astressin2-B vs that of antisauvagine-30 is demonstrated in the CRF2-mediated animal model whereby the inhibition of gastric emptying of a solid meal in mice by urocortin administered intraperitoneally at time zero is antagonized by the administration of astressin2-B but not by antisauvagine-30 at times −3 and −6 h while both peptides are effective when given 10 min before urocortin.


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