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Search for lipidized PrRP analogs with strong anorexigenic effect: In vitro and in vivo studies
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SYSNO ASEP 0570639 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Search for lipidized PrRP analogs with strong anorexigenic effect: In vitro and in vivo studies Author(s) Strnadová, Veronika (UOCHB-X)
Karnošová, Alena (UOCHB-X)
Blechová, Miroslava (UOCHB-X)
Neprašová, Barbora (UOCHB-X)
Holá, Lucie (UOCHB-X) ORCID
Němcová, Anna (UOCHB-X)
Myšková, Aneta (UOCHB-X)
Sýkora, D. (CZ)
Železná, Blanka (UOCHB-X) RID, ORCID
Kuneš, Jaroslav (UOCHB-X) ORCID, RID
Maletínská, Lenka (UOCHB-X) RID, ORCIDArticle number 102319 Source Title Neuropeptides. - : Elsevier - ISSN 0143-4179
Roč. 98, April (2023)Number of pages 12 s. Language eng - English Country GB - United Kingdom Keywords prolactin-releasing peptide ; lipidization ; GPR10 ; NPFF-R2 ; NPFF-R1 ; ERK ; Akt activation ; stability ; food intake OECD category Physiology (including cytology) R&D Projects GA21-03691S GA ČR - Czech Science Foundation (CSF) LX22NPO5104 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support UOCHB-X - RVO:61388963 UT WOS 000963271700001 EID SCOPUS 85149800491 DOI 10.1016/j.npep.2022.102319 Annotation Prolactin-releasing peptide (PrRP) is an anorexigenic neuropeptide that attenuates food intake and increases energy expenditure. We designed three series of new lipidized PrRP31 analogs of different lengths of fatty acids attached at amino acids 1 or 11 directly or via linkers, part of them acetylated at the N-terminus and/or modified with dichlorophenylalanine (PheCl2) at the C-terminus. We tested their affinity for and activation of signaling pathways relevant to receptors GPR10, NPFF-R2, and NPFF-R1, effect on food intake in fasted or freely fed mice and rats, and stability in rat plasma. We aimed to select a strong dual GPR10/NPFF-R2 agonist whose affinity for NPFF-1 was not enhanced. The selected potent analog was then tested for body weight-lowering potency after chronic administration in mice with diet-induced obesity. PrRP31 analogs lipidized by monocarboxylic fatty acids showed strong dual affinity for both GPR10 and NPFF-R2 and activated MAPK/ERK1/2, Akt and CREB in cells overexpressing GPR10 and NPFF-R2. The selected analog stabilized at N- and C-termini and palmitoylated through the TTDS linker to Lys11 is a powerful dual agonist GPR10/NPFF-R2 at not enhanced affinity for NPFF-R1. It showed strong anti-obesity properties in mice with diet-induced obesity and became a potential compound for further studies. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434 Year of Publishing 2024 Electronic address https://doi.org/10.1016/j.npep.2022.102319
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