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Lipidated peptides as Anti-obesity agents

a technology of lipidated peptides and anti-obesity agents, which is applied in the direction of peptide/protein ingredients, drug compositions, and metabolic disorders, etc., can solve the problems of increasing obesity, no effective therapies available, and current medications are typically associated with adverse side effects

Inactive Publication Date: 2016-11-17
USTAV ORGANICKE CHEM A BIOCHEM AKADE VED CR V V I
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes lipidated analogs of prolactin-releasing peptide that have improved biological activity and stability. These analogs can be used for the treatment of medical conditions such as infertility and sexual dysfunction. The lipidated peptides have a general formula that includes a fatty acid attached to the N-terminal amino acid through an amide bond. The fatty acid can be chosen from C6 to C18 and can be further modified by other amino acids or other molecules. The lipidated peptides can be administered alone or in combination with other compounds to enhance their effects. The technical effects of the patent text include improved stability and biological activity of the lipidated prolactin-releasing peptide analogs.

Problems solved by technology

In both the developing and developed countries, obesity is an increasingly growing problem, for which no effective therapies are available.
Current medications are typically associated with adverse side effects.
It is, however, associated with adverse effects, such as diarrhea.

Method used

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  • Lipidated peptides as Anti-obesity agents
  • Lipidated peptides as Anti-obesity agents
  • Lipidated peptides as Anti-obesity agents

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of the PrRP Peptides and PrRPanalogs

[0233]The peptides were synthesized using the method of solid phase synthesis according to Maixnerová et al. (Maixnerová, J., et al., “Structure-activity relationship of CART (cocaine- and amphetamine-regulated transcript) peptide fragments,”Peptides, 28:1945-1953, 2007) utilizing the Fmoc strategy on the ABI 433A synthesizer (Applied Biosystems, Foster City, Calif., USA). Lipidation with the appropriate fatty acid was performed before cleaving the peptide off the resin as reported in Maletínská, L., et al., “Characterization of new stable ghrelin analogs with prolonged orexigenic potency,”J Pharmacol Exp Ther, 340:781-786, 2012.

[0234]The peptide PrRP31 was iodinated with Na125I using Iodo-Gen (Picrce, Rockford, Ill., USA) according to the published procedure (Maixnerová et al., 2011). Monoiodinated peptide was stored in aliquots at −20° C. and was used up in binding assays within one month.

[0235]Table 1 describes the structures of PrRP3...

example 2

Competitive Binding Experiments

[0236]Competitive binding experiments were performed according to Motulsky and Neubig (Motulsky, A., et al., “Analyzing radioligand binding data,”Curr Protoc Neurosci, Chapter 7, Unit 7.5, 2002).

[0237]Binding experiments were conducted with rat pituitary cells and CHO cells as follows:

[0238]The rat pituitary cell line RC-4B / C (ATCC, Manassas, USA) was grown on 24-well plates which had their bottom coated with polyethyleneimine. The cells were grown to the optimal density of 300-450 thousand per well. The following agents were used for the experiment: binding buffer (20 mmol·l−1 HEPES, pH 7.4; 118 mmol·l−1 NaCl, 4.7 mmol·l−1 KCl, 5 mmol·l−1 MgCl2, 5.5 mmol·l−1 glucose, 1 mg / ml BSA, 0.1 mg / ml BPTI), unlabelled analogs of PrRP of final concentration within 10−11 to 10−4 mol·l−1, and rat 125I—PrRP31 of final concentration of 10−10 mol·l−1 (Maixnerová et al., 2011).

[0239]CHO cells with transfected human PrRP receptor, GPR10 (Perkin Elmer, USA) were grown on...

example 3

Cellular Signaling

[0245]RC-4B / C cells, which were used to determine if lipidated PrRP20 analogs are able to initiate the MAPK / ERK1 / 2 signaling pathway, were grown in 6-well plates up to the optimal density of 700-900 cells per well. Seventeen hours before sample harvest, the growth medium was replaced by a serum-free medium lacking epidermal growth factor (EGF). The respective lipidated PrRP analog was added to each well in the final concentration of 10−6 mol·l−1. After a 5 minute incubation at 37° C., the plate was placed on ice and each well was rinsed three times with PBS pH 7.4 (137 mmol·l−1 NaCl, 2.7 mmol·l−1 KCl, 8 mmol·l−1 Na2HPO4.2H2O a 1.76 mmol·l−1 KH2PO4) and cooled to 4° C. The cells were then solubilized in a sample buffer (62.5 mmol·l−1 Tris-HCl pH 6.8, 10% glycerol, 2% SDS, 0.01% bromophenol blue, 5% merkaptoethanol, 50 mmol·l−1 NaF and 1 mmol·l−1 Na3VO4), and collected into microtubes and frozen at −20° C. Samples were collected in at least three independent experime...

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Abstract

Lipidated peptides, analogs of both forms of the prolactin-releasing peptide. PrRP31 and PrRP20, represent anorexigenic compounds that lower food intake and function in the brain after peripheral administration. The analogs PrRP31 and PrRP20 lipidated at the N-terminus by myristic or palmitic acids bind with high affinity to the endogenous receptor GPR10 in the rat pituitary cell line RC-4B / C and CHO cell line with transfected human receptor. These lipidated peptides also significantly decrease, in a dose-dependent manner, the food intake in fasted mice and have similar effects in comparable doses as centrally administered natural PrRP31, these effects are, however, stronger and longer lasting. Lipidation of an effective anorexigenic neuropeptide PrRP induces a central effect after peripheral administration and thus makes the lipidated analogs of PrRP a promising anti-obesity drug.

Description

CROSS-REFERENCE[0001]This application claims the benefit of Czech Republic Application No. PV 2012-476, filed Jul. 12, 2012, which is incorporated herein by reference.FIELD OF THE INVENTION[0002]The embodiments described herein relate to lipidated analogs of prolactin-releasing peptides and the use of these analogs as anorexigenic compounds that lower food intake. The synthesis of these lipidated peptides is described herein, as well as their pharmacological effects in vitro and in vivo.BACKGROUND OF THE INVENTION[0003]In both the developing and developed countries, obesity is an increasingly growing problem, for which no effective therapies are available. Current medications are typically associated with adverse side effects. For example, the only medication available in the Czech Republic is Orlistat, an inhibitor of intestinal lipase which lowers the absorption of lipids from the small intestine. It is, however, associated with adverse effects, such as diarrhea. Sibutramine, a se...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/22A61K47/48
CPCA61K47/48046A61K38/2257A61K47/543C07K14/575A61P3/04
Inventor MALETINSKA, LENKAZELEZNA, BLANKABLECHOVA, MIROSLAVAPOPELOVA, ANDREA
Owner USTAV ORGANICKE CHEM A BIOCHEM AKADE VED CR V V I
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