Compositions and methods for treating obesity, obesity related disorders and for inhibiting the infectivity of human immunodeficiency virus

a technology composition, which is applied in the field of compositions and methods for treating obesity, obesity related disorders and inhibiting the infectivity of human immunodeficiency virus, can solve the problems of obesity and its associated complications, serious contributors to increased morbidity and mortality, and heart attack, stroke, etc., and achieves the effects of reducing fat accumulation and weight gain, reducing the number of adipocytes, and reducing the number of fat cells

Inactive Publication Date: 2009-03-05
NEW YORK UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0006]In accordance with the broadest aspect of the invention, methods and compositions comprising oleuropein, or an analogue or derivative thereof, or the major metabolites of oleuropein including oleuropein aglycone, hydroxytyrosol, and elenolic acid or their analogues, or derivatives thereof, or an iridoid glycoside, or a secoiridoid glycoside or their analogues or derivatives thereof, or any combination of the foregoing including but not limited to olive leave extract, are disclosed for treating obesity and obesity-related conditions or disorders, as well as for inhibiting the infectivity of HIV. In particular, these compositions modulate adipogenesis, lipodystrophy, reduce fat accumulation and weight gain. These agents also prevent HIV viral fusion/entry into a host cell and bind the catalytic site of the HIV integrase. Thus, these agents provide an advantage over other anti-viral therapies in that both viral entry and integration are inhibited. They exert their effect by modulating adipocyte differentiation (adipogenesis), de-differentiation, transdifferentiation, and by decreasing the number of adipocytes (fat cells), or by modulating adipocyte metabolism (lipid synthesis, storage, accumulation, and utilization) so as to decrease fat accumulation and decrease the size of the fat cell (decrease fat mass), increase fat burning and expenditure. These compositions also have an effect on adipogenic, lipogenic and lipolytic gene/gene product expression, perturbation of pre-adipocyte to ad...

Problems solved by technology

Obesity, which is defined in general terms as an excess of body fat relative to lean body mass, is now a world wide epidemic, and is one of the most serious contributors to increased morbidity and mortality.
These abnormalities predispose the vasculature to injury, cellular proliferation and lipid oxidation, with resulting atherosclerosis leading to heart attack, stroke, and peripheral vascular diseases.
Thus, obesity and its associated complications continue to be a major problem throughout the worldwide health care system.
To date, these approaches have been limited to diet and exercise (therapeutic lifestyle changes), surgical procedures such as gastric bypass, and pharmacologic agents.
Drug treatment for obesit...

Method used

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  • Compositions and methods for treating obesity, obesity related disorders and for inhibiting the infectivity of human immunodeficiency virus
  • Compositions and methods for treating obesity, obesity related disorders and for inhibiting the infectivity of human immunodeficiency virus
  • Compositions and methods for treating obesity, obesity related disorders and for inhibiting the infectivity of human immunodeficiency virus

Examples

Experimental program
Comparison scheme
Effect test

example 1

Modulation of Adipogenesis and Lipodystrophy by Oleuropein

Oleuropein Modulates Adipocyte Differentiation

Methods

[0303]Human mesenchymal stem cells (hMSCs) at 104 cells / cm2 were cultured in MSC growth medium first to confluence. Adipogenesis was induced two days post confluence by culturing the cells in adipogenic medium (AIM) containing 10 μM dexamethasone, 1 μg / ml insulin, and 0.5 mM 3-isobutyl-1-methylxanthine, in the absence and presence of oleuropein at 1, 10 and 100 μM. Fresh culture medium was changed every 3 days. Full differentiation of hMSC to adipocytes was detected by Oil Red 0 staining at day 12. Gene expression was monitored by RT-PCR, using primers shown in Table 3.

Results

[0304]It was determined that oleuropein down-regulates adipocyte differentiation, fat accumulation and adipogenic gene expression in human mesenchymal stem cells (hMSCs). As seen in FIG. 1, hMSCs grown in control medium do not stain with Oil Red O (counterstained with hematoxylin), while hMSCs grown in...

example 2

Modulation of Endothelial Dysfunction and Atherosclerosis by Oleuropein

[0308]Oleuropein Reduces Diet-Induced Atherosclerosis in the Western Diet-Fed apoE ko Mouse

Methods

[0309]It was previously demonstrated that oleuropein and OLE, following administration to mice, could be detected in the blood and urine by LC-MS. To test whether oleuropein reduces diet-induced atherosclerosis, oleuropein was administered to apoE ko mice at various doses from 0.25 mg / ml, 2.5 mg / ml, and 25 mg / ml in the drinking water followed by feeding them with a Western diet containing 42% of calories from fat (Harlan-Teklad). At the 4 month time-point for the 0.25 mg / ml dose (daily dose 1.25 mg), serum levels of oleuropein achieved with this dose are comparable to those in animals fed a diet supplemented with olive oil.

[0310]The mice were sacrificed, blood and tissues collected. Aortas were dissected from the aortic valve to the iliac bifurcation, opened longitudinally, and pinned to a black wax surface. Atherosc...

example 3

Computational Approaches to New Treatments for Obesity

Methods

[0313]Detailed theoretical and computational analysis for binding of oleuropein to PPARδ, PPARγ and PPARα was performed, using an approach that combines AutoDock, MD and MM-PBSA calculations. We used the crystal structure of PPARδ and PPARγ ligand binding domains. The large ligand-binding site is formed by several α-helices, including the C-terminal AF-2 helix. We first used molecular docking to generate several distinct binding orientations, and performed molecular dynamics simulation to further relax the complex. Then, we applied MM-PBSA to estimate the affinity for each binding mode. The binding modes with the lowest free energy are expected to be the most favorable. We then analyzed the detailed interactions based on these binding modes.

Oleuropein Mimics the Binding Mode of High Affinity Ligands for PPARδ

[0314]FIG. 5a shows docking of oleuropein to PPARδ in the energetically most favorable binding mode (II), with free ...

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Abstract

The present invention relates to methods and pharmaceutical compositions for treating obesity or obesity-related disorders in a subject suffering from or predisposed to developing obesity or an obesity-related disorder, or for inhibiting the infectivity of HIV, by administering oleuropein, an analogue or derivative thereof, or the major metabolites of oleuropein including oleuropein aglycone, hydroxytyrosol, and elenolic acid or their analogues, or derivatives thereof, an iridoid glycoside, or a secoiridoid glycoside or analogues or derivatives thereof, or any combination of the foregoing including olive leave extract. The invention also relates to methods for screening/diagnosing a subject having, or predisposed to having obesity or a related disorder by measuring the expression profiles of an adipogenic gene selected from PPARγ2, LPL and αP2 gene and gene product, or other adipogenic, lipogenic, or lipolytic genes and gene products in an individual. The invention further provides for screening for novel oleuropein analogues.

Description

FIELD OF THE INVENTION[0001]The present invention relates generally to methods and compositions for modulating the body weight of mammals including animals and humans, and more particularly to materials identified herein as modulators of weight, and the use of these materials for treating obesity and disorders related to obesity and to the diagnostic and therapeutic uses to which such modulators may be put. The present invention also relates to methods and compositions for inhibiting the infectivity of human immunodeficiency virus (HIV).BACKGROUND OF THE INVENTION[0002]Obesity, which is defined in general terms as an excess of body fat relative to lean body mass, is now a world wide epidemic, and is one of the most serious contributors to increased morbidity and mortality. Obesity is prevalent in the United States, affecting more than 61% of the total population (Flegal, et al., Overweight and Obesity in the United States: Prevalence and Trends, 1960-1994. Int J Obes 22:39-47, 1998)...

Claims

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Application Information

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IPC IPC(8): A61K36/00A61K31/351A61K31/70A61K38/28A61K31/4439A61K31/435A61K31/366A61K31/7036A61P3/00A61P31/12A61K31/175A61K31/445A61K31/404A61K31/40A61K31/427A61K31/155A61K31/05
CPCA61K31/05A61K45/06A61K31/175A61K31/351A61K31/366A61K31/40A61K31/404A61K31/427A61K31/435A61K31/4439A61K31/445A61K31/70A61K31/7036A61K38/28A61K31/7048A61K31/155A61P3/00A61P31/12A61K36/00
Inventor LEE-HUANG, SYLVIAHUANG, PAUL L.HUANG, PHILIP LINZHANG, DAWEIZHANG, JOHN Z.H.CHANG, YOUNG TAELEE, JAE WOOKBAO, JUSUN, YONGTAO
Owner NEW YORK UNIV
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