Abstract
Analogs of anorexigenic neuropeptides, such as prolactin-releasing peptide (PrRP), have a potential as new anti-obesity drugs. In our previous study, palmitic acid attached to the N-terminus of PrRP enabled its central anorexigenic effects after peripheral administration. In this study, two linkers, γ-glutamic acid at Lys11 and a short, modified polyethylene glycol at the N-terminal Ser and/or Lys11, were applied for the palmitoylation of PrRP31 to improve its bioavailability. These analogs had a high affinity and activation ability to the PrRP receptor GPR10 and the neuropeptide FF2 receptor, as well as short-term anorexigenic effect similar to PrRP palmitoylated at the N-terminus. Two-week treatment with analogs that were palmitoylated through linkers to Lys11 (analogs 1 and 2), but not with analog modified both at the N-terminus and Lys11 (analog 3) decreased body and liver weights, insulin, leptin, triglyceride, cholesterol and free fatty acid plasma levels in a mouse model of diet-induced obesity. Moreover, the expression of uncoupling protein-1 was increased in brown fat suggesting an increase in energy expenditure. In addition, treatment with analogs 1 and 2 but not analog 3 significantly decreased urinary concentrations of 1-methylnicotinamide and its oxidation products N-methyl-2-pyridone-5-carboxamide and N-methyl-4-pyridone-3-carboxamide, as shown by NMR-based metabolomics. This observation confirmed the previously reported increase in nicotinamide derivatives in obesity and type 2 diabetes mellitus and the effectiveness of analogs 1 and 2 in the treatment of these disorders.
Highlights
The identification of new substances with targeted anti-obesity potencies is needed, as several anti-obesity drugs, namely derivatives of neurotransmitters, have been withdrawn from the market because of significant side effects
Three palmitoylated analogs of PrRP31 were prepared by the attachment of palmitic acid through a linker (γ-glutamic acid or 1,13-diamino-4,7,10-trioxatridecan-succinamic acid (TTDS)) to the side chain amino group of Lys11
We explored the biological properties of newly designed analogs of PrRP31 that were palmitoylated through a linker of gamma-glutamic acid or a short modified polyethylene glycol at position 11, as well as an analog with two palmitoyls, one at the N-terminus and one at position 11
Summary
The identification of new substances with targeted anti-obesity potencies is needed, as several anti-obesity drugs, namely derivatives of neurotransmitters, have been withdrawn from the market because of significant side effects. Analogs of anorexigenic peptides seem to be a better alternative for the development of new anti-obesity drugs. Liraglutide, a glucagon-like peptide-1 (GLP-1) analog acylated with palmitic acid that was originally developed as a type-2 diabetes mellitus (T2DM) drug, has recently been approved in the U.S.A for obesity treatment (Saxenda). In addition to GLP-1, pancreatic polypeptide (PP) and peptide YY (PYY)—peptides of gut origin affecting the gastrointestinal tract—have central anorexigenic effects (gut-brain peptides) and have been evaluated as possible treatments for obesity. Several brain anorexigenic neuropeptides such as α-melanocyte stimulating hormone (α-MSH), cocaine- and amphetamine-regulated transcript (CART) peptide or prolactin releasing peptide (PrRP) originate in the brain where they have anorexic actions. An α-MSH analog modified with a fatty acid has been shown to be a stable substance with strong anorexigenic effect [1]. The CART peptide receptor has not yet been identified, which makes it pharmacologically less desired [3]
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