title: Characterization of new stable ghrelin analogs with prolonged orexigenic potency.
abstract: Ghrelin, the only known peripherally produced and centrally acting peptide that stimulates food intake, is synthesized primarily in the stomach and acts through the growth hormone secretagogue receptor (GHS-R1a). In addition to its orexigenic effect, ghrelin stimulates the release of growth hormone (GH). In this study, we investigated the biological properties of full-length and shortened ghrelin analogs in which octanoylated Ser(3) is replaced with an octanoic acid moiety coupled to diaminopropionic acid (Dpr). Ghrelin analogs stabilized with Dpr(N-octanoyl) in position 3 and noncoded amino acids in position 1 (sarcosine) and/or position 4 (naphthylalanine or cyclohexylalanine) were found to possess affinities similar to those of ghrelin for cell membranes with transfected GHS-R1a. In vivo, the prolonged orexigenic effects of analogs containing Dpr(N-octanoyl)(3) compared with that of ghrelin in adult mice and a similar impact on GH secretion in young mice were found. Full-length [Dpr(N-octanoyl)(3)]ghrelin and its analogs with a noncoded amino acid in position 1 and/or 4 showed significantly prolonged stability in blood plasma compared with that of ghrelin. Ghrelin analogs with a prolonged orexigenic effect are potential treatments for GH deficiency or cachexia that accompanies chronic diseases. Desoctanoylated ghrelin analogs and N-terminal penta- and octapeptides of ghrelin did not show any biological activity.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Maletínská
authors.forename: Miroslava
authors.initials: M
authors.lastname: Pýchová
authors.forename: Martina
authors.initials: M
authors.lastname: Holubová
authors.forename: Miroslava
authors.initials: M
authors.lastname: Blechová
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Demianová
authors.forename: Tomáš
authors.initials: T
authors.lastname: Elbert
authors.forename: Blanka
authors.initials: B
authors.lastname: Železná
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004435:Eating / Q000187:drug effects*; D054439:Ghrelin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D013006:Growth Hormone / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D054440:Receptors, Ghrelin / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D054439:Ghrelin; D054440:Receptors, Ghrelin; D013006:Growth Hormone