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Modulation of peroxisome proliferation-activated receptors

A technology of compounds and modulators, applied in the field of DNA vectors, can solve the problems of limited therapeutic efficacy and side effects of PPAR

Inactive Publication Date: 2007-02-21
ABGENOMICS COOPERATIEF U A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most PPAR treatments have limited efficacy and have significant side effects

Method used

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  • Modulation of peroxisome proliferation-activated receptors
  • Modulation of peroxisome proliferation-activated receptors
  • Modulation of peroxisome proliferation-activated receptors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 3

[0163] Example 3 PGR3 / ZADH2 Small Molecule Inhibitors

[0164]The recombinant human PGR3 / ZADH2 protein was expressed and its enzyme activity was detected. Similar to murine PGR3 / ZADH2, recombinant human PGR3 / ZADH2 has 15-ketoprostaglandin-Δ 13 - Reductase activity and catalyzes the conversion of 15-ketoprostaglandins to 13,14-dihydro-15-ketoprostaglandins.

[0165] The inhibitory effect of compounds 1-49 on PGR3 / ZADH2 activity was tested. These compounds are available commercially (eg, from Sigma-Aldrich, St. Louis, MO) or can be prepared from methods well known in the art. Inhibition assays were performed as described above. Different concentrations of PGR3 / ZADH2 inhibitors were added to the reaction mixture and incubated at 37°C for 2 hours.

[0166] More specifically, 50 μM of compounds 8, 12, 13, and 27, and 25 μM of trifluorobenzyl-2-hydroxycinnamic acid (compound 22) were added to the PGR3 / ZADH2 enzyme reaction system, and the enzymatic reduction of 15-ketoprostatic ...

Embodiment 4

[0170] Effect of Example 4 PGR3 / ZADH2 Inhibitor on Insulin Sensitivity

[0171] The effect of two of the aforementioned PGR3 / ZADH2 inhibitors, compounds 12 and 28, on insulin sensitivity was examined as follows. 3T3-L1 cells were induced to differentiate in the same manner as above. According to the method described by Finga et al. (Endocrinology 134:728-735), by measuring the response to 2-deoxy-D-[ 3 H] Glucose uptake was performed in a glucose transport assay. 1.67M inhibitor or 45nMPPAR-γ agonist, Avandia, was added to the cells.

[0172] 10M Cytochalasin B was used to measure background levels of glucose uptake. 100 nM insulin was used to stimulate glucose uptake. Insulin treatment alone increases glucose uptake by more than 10-fold in differentiated 3T3-L1 cells. Glucose uptake was increased 30-fold in the presence of any two PGR3 / ZADH2 inhibitors. The ability of these inhibitors to increase glucose uptake was found to be comparable to that of AVANDIA.

[0173] Th...

Embodiment 5

[0176] Example 5 RNA interference

[0177] Silencing of PGR3 / ZADH2 expression by RNA interference in 3T3-L1 preadipocytes. To generate vectors encoding interfering RNAs targeting PGR3 / ZADH2, standard methods were used to synthesize vectors containing 5'-GAT CCG TGC CAC GTT ATC GGA ACC TTC AAG AGA GGT TCC GAT AAC GTGGCA CTT TTT TGG AAA-3' (SEQ ID NO: 9; forward primer) and oligonucleotides of AGC TTT TCC AAA AAAGTG CCA CGT TAT CGG AAC CTC TCT TGA AGG TTC CGA TAA CGT GGC ACG-3' (SEQ ID NO: 10; reverse primer). They were then annealed and introduced into the linear siRNA expression vector, pSilencer™ neo (catalog # 5764, Ambion). The siRNA expression vector was then introduced into 3T3-L1 preadipocytes by electroporation. Stable transfected clones were isolated using G418 selection. PGR3 / ZADH2 mRNA levels in these claims were then detected using standard RT-PCR. It was found that PGR3 / ZADH2 mRNA transcript levels were suppressed.

[0178] The clones described above were used...

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Abstract

Method of treating diseases associated with peroxisome proliferator-activated receptors by administering to a subject in need thereof an effective amount of 15-ketoprostaglandin-delta 13 - Reductase modulators. Also disclosed is a method of identifying a compound that inhibits the reductase activity, and a method of lowering blood glucose levels by administering to a subject an effective amount of the reductase inhibitor.

Description

[0001] Cross References to Related Applications [0002] Pursuant to 35 U.S.C. §119(e), this application claims priority to U.S. Provisional Application Serial No. 60 / 707,897, filed August 12, 2005, the entire contents of which are hereby incorporated by reference. Background technique [0003] Peroxisome proliferator-activated receptors (PPARs) belong to a family of nuclear receptors that regulate fat and glucose metabolism. Three mammalian PPARs have been identified, namely PPAR-α, PPAR-γ and PPAR-Δ. Activation by dietary fatty acids or their metabolic derivatives, PPARs can initiate transcriptional temporal cascades that result in altered fat and glucose metabolism. For example, through activation, PPAR-γ, which is highly expressed in adipose tissue, promotes glucose uptake and lowers blood glucose levels. [0004] Based on their role in fat and glucose metabolism, PPARs are predicted to be therapeutic targets in diseases such as type II diabetes, obesity, dyslipidemia, c...

Claims

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Application Information

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IPC IPC(8): C12N9/02C07K14/435C12N15/53C12N15/12C07K16/40A61K38/44A61K38/17A61K48/00A61K39/395A61P3/10A61P3/04A61P3/06A61P9/00A61P35/00
CPCC07K14/70567C12N9/0004C12N9/0006A61K31/33A61P29/00A61P3/00A61P3/04A61P35/00A61P3/06A61P9/00A61P9/10A61P3/10C07K14/705
Inventor 林荣华庄立民
Owner ABGENOMICS COOPERATIEF U A
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