Abstract
Prolactin-releasing peptide (PrRP) is an endogenous neuropeptide involved in appetite regulation and energy homeostasis. PrRP binds with high affinity to G-protein coupled receptor 10 (GPR10) and with lesser activity towards the neuropeptide FF receptor type 2 (NPFF2R). The present study aimed to develop long-acting PrRP31 analogues with potent anti-obesity efficacy. A comprehensive series of C18 lipidated PrRP31 analogues was characterized in vitro and analogues with various GPR10 and NPFF2R activity profiles were profiled for bioavailability and metabolic effects following subcutaneous administration in diet-induced obese (DIO) mice. PrRP31 analogues acylated with a C18 lipid chain carrying a terminal acid (C18 diacid) were potent GPR10-selective agonists and weight-neutral in DIO mice. In contrast, acylation with aliphatic C18 lipid chain (C18) resulted in dual GPR10-NPFF2R co-agonists that suppressed food intake and promoted a robust weight loss in DIO mice, which was sustained for at least one week after last dosing. Rapid in vivo degradation of C18 PrRP31 analogues gave rise to circulating lipidated PrRP metabolites maintaining dual GPR10-NPFF2R agonist profile and long-acting anti-obesity efficacy in DIO mice. Combined GPR10 and NPFF2R activation may therefore be a critical mechanism for obtaining robust anti-obesity efficacy of PrRP31 analogues.
Highlights
Prolactin-releasing peptide (PrRP) is an endogenous neuropeptide involved in appetite regulation and energy homeostasis
PrRP31 analogues were profiled for functional G-protein coupled receptor 10 (GPR10) vs. NPFF2R activity, with a subset of analogues selected for further characterization in diet-induced obese (DIO) mice (Fig. 1)
A comprehensive structure–activity relationship (SAR) study was performed with the aim to evaluate peptide protraction effects on GPR10 and NPFF2R activation
Summary
Prolactin-releasing peptide (PrRP) is an endogenous neuropeptide involved in appetite regulation and energy homeostasis. PrRP31 analogues acylated with a C18 lipid chain carrying a terminal acid (C18 diacid) were potent GPR10-selective agonists and weight-neutral in DIO mice. The RF-amide family consists of five subfamilies of peptides, i.e. PrRP, neuropeptides FF (NPFF), RF-amide related peptide, kisspeptins and pyroglutamylated RF-amide peptides These peptides share a common C-terminal Arg-Phe-amide motif that serves as pharmacophore for activation of their corresponding G-protein coupled receptors (GPCRs)[1]. Attachment of fatty acids as albumin tags to bioactive peptides to prolong their duration of action is a common strategy to afford peptide-based therapies This approach has been widely exploited for development of peptide hormone analogues suitable for diabetes and obesity treatment[24–26]. Because C18 fatty acid derivatization further stabilizes against systemic clearance[24], this prompted us to explore various C18 lipidation strategies to achieve long-acting PrRP31 analogues with potent body weight lowering efficacy
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