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Search for lipidized PrRP analogs with strong anorexigenic effect: In vitro and in vivo studies

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    0571848 - FGÚ 2024 RIV GB eng J - Journal Article
    Strnadová, V. - Karnošová, A. - Blechová, M. - Neprašová, B. - Holá, L. - Němcová, A. - Myšková, A. - Sýkora, D. - Železná, B. - Kuneš, Jaroslav - Maletínská, L.
    Search for lipidized PrRP analogs with strong anorexigenic effect: In vitro and in vivo studies.
    Neuropeptides. Roč. 98, April (2023), č. článku 102319. ISSN 0143-4179. E-ISSN 1532-2785
    R&D Projects: GA ČR(CZ) GA21-03691S; GA MŠk(CZ) LX22NPO5104
    Institutional support: RVO:67985823
    Keywords : prolactin-releasing peptide * lipidization * GPR10 * NPFF-R2 * NPFF-R1 * ERK * Akt activation * stability * food intake
    OECD category: Physiology (including cytology)
    Impact factor: 2.9, year: 2022
    Method of publishing: Open access
    https://doi.org/10.1016/j.npep.2022.102319

    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.
    Permanent Link: https://hdl.handle.net/11104/0342764

     
     
Number of the records: 1  

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