PT  - JOURNAL ARTICLE
AU  - Martina Holubová
AU  - Miroslava Blechová
AU  - Anna Kákonová
AU  - Jaroslav Kuneš
AU  - Blanka Železná
AU  - Lenka Maletínská
TI  - In Vitro and In Vivo Characterization of Novel Stable Peptidic Ghrelin Analogs: Beneficial Effects in the Settings of Lipopolysaccharide-Induced Anorexia in Mice
AID  - 10.1124/jpet.118.249086
DP  - 2018 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 422--432
VI  - 366
IP  - 3
4099  - http://jpet.aspetjournals.org/content/366/3/422.short
4100  - http://jpet.aspetjournals.org/content/366/3/422.full
SO  - J Pharmacol Exp Ther2018 Sep 01; 366
AB  - Ghrelin, the only known orexigenic gut hormone produced primarily in the stomach, has lately gained attention as a potential treatment of anorexia and cachexia. However, its biologic stability is highly limited; therefore, a number of both peptide and nonpeptide ghrelin analogs have been synthesized. In this study, we provide in vitro and in vivo characterization of a series of novel peptide growth hormone secretagogue receptor (GHS-R1a) agonists, both under nonpathologic conditions and in the context of lipopolysaccharide (LPS)-induced anorexia. These analogs were based on our previous series modified by replacing the Ser3 with diaminopropionic acid (Dpr), the N-terminal Gly with sarcosine, and Phe4 with various noncoded amino acids. New analogs were further modified by replacing the n-octanoyl bound to Dpr3 with longer or unsaturated fatty acid residues, by incorporation of the second fatty acid residue into the molecule, or by shortening the peptide chain. These modifications preserved the ability of ghrelin analogs to bind to the membranes of cells transfected with GHS-R1a, as well as the GHS-R1a signaling activation. The selected analogs exhibited long-lasting and potent orexigenic effects after a single s.c. administration in mice. The stability of new ghrelin analogs in mice after s.c. administration was significantly higher when compared with ghrelin and [Dpr3]ghrelin, with half-lives of approximately 2 hours. A single s.c. injection of the selected ghrelin analogs in mice with LPS-induced anorexia significantly increased food intake via the activation of orexigenic pathways and normalized blood levels of proinflammatory cytokines, demonstrating the anti-inflammatory potential of the analogs.