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Synthetic apolipoprotein e mimicking polypeptides and methods of use

a polypeptide and synthetic technology, applied in the field of synthetic apolipoproteins and polypeptide mimics, can solve the problems of increased plasma cholesterol levels, increased oxidative stress, increased triglyceride-rich lipoproteins, etc., and achieves the effect of improving endothelial function and increasing pon activity

Inactive Publication Date: 2012-09-27
UAB RES FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Epidemiological studies indicate that increased plasma cholesterol levels increase the risk for atherosclerosis.
There is also growing evidence that triglyceride-rich lipoproteins may adversely affect endothelial function and increase oxidative stress by promoting the production of small, dense LDL and by reducing high-density lipoprotein (HDL) levels (Marais, D., Curr. Opin. Lipidol. 2000, 11:597-602).
However, these peptides do not enhance LDL degradation.
There are no agents available which reduce cholesterol via the binding mechanisms of lipoproteins.

Method used

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  • Synthetic apolipoprotein e mimicking polypeptides and methods of use
  • Synthetic apolipoprotein e mimicking polypeptides and methods of use
  • Synthetic apolipoprotein e mimicking polypeptides and methods of use

Examples

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Effect test

example 1

Effect of Cationic Dual-Domain Peptides on Atherogenic Lipoprotein Uptake

[0273]The effect of the peptide Ac-LRKLRKRLLR-18A-NH2 (Ac-hE18A-NH2; SEQ ID NO: 12) in HepG2 cells and in dyslipidemic mouse models has been previously described (5, 6, 7, 8, 9). These studies demonstrated that the peptide Ac-hE-18A-NH2 (and not LRKLRKRLLR or Ac-18A-NH2) associates with atherogenic apo B-containing lipoproteins in human plasma. It was also shown that the peptide is able to enhance the uptake and degradation of LDL and VLDL in HepG2 cells Datta, G. et al. Biochemistry 39:213-220 2000). Preliminary results have shown that LDL-receptor was not involved in the clearance of plasma cholesterol. In dyslipidemic mouse models, studies showed that the peptide is able to associate with apo B48-containing lipoproteins and enhance their uptake and degradation (Datta, G. et al. Biochemistry 39:213-220 2000). In C57BL6 mice fed an atherogenic diet, apo E null mice, apo E(null)-LDL-R(null) double knockout mice...

example 2

Ac-hE-18A-NH2 Inhibits Atherosclerosis in Apo E Null Mice

[0274]Atherosclerosis inhibition studies in apo E null mice that develop atherosclerosis spontaneously were also performed. Retroorbital administration of Ac-hE-18A-NH2 (50 μg / mouse, 3 times weekly) for four weeks into sixteen week old female apo E null mice showed decreased lesion by 40% (p value<0.001) compared to the control group (n=11 in control and n=12 in peptide administered group). In this administration procedure, there was no loss of animals and no visible injury to animals was observed, despite multiple administration (of a total of 12 administrations). Lesion analysis was performed using the en face preparations. Sixteen week old mice would have well established lesions. These results (FIG. 2) show that the peptide is able to inhibit lesion formation in apo E null mice. These results are in agreement with the peptide being antiatherogenic. Detailed studies on the mechanism of the inhibition of atherosclerosis are ...

example 3

[0275]It has been shown that a portion of apo E on triglyceride-rich lipoproteins, as well as on HDL is internalized and recycled (Swift, L. L. et al., J. Biol. Chem. 276:22965-22970 2001; Farkas, M. H. et al., J. Lipid Res. 45: 1546-1554 2004). Liver cells can internalize apo E which is eventually re-released. Administration (i.v) of 100 μg of the peptide Ac-hE-18A-NH2 in to C57BL / 6J mice (n=9 in each group) fed an atherogenic diet showed a biphasic effect on plasma cholesterol levels. Initially peptide decreased plasma cholesterol by >65%. Lower total cholesterol levels were observed even after 8 days in the peptide administered group compared to the control group despite continued atherogenic diet administration (FIG. 3). Effect on plasma cholesterol is seen even after the disappearance of the peptide from plasma. It is possible that the apo E-mimetic peptide is recycled. To understand the mechanism by which the peptide is able to exert such a dramatic effect, the effects of the ...

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Abstract

The present invention provides novel synthetic apolipoprotein E (ApoE)-mimicking peptides wherein the receptor binding domain of apolipoprotein E is covalently linked to 18A, the well characterized lipid-associating model class A amphipathic helical peptide, or a modified version thereof. Such peptides enhance low density lipoprotein (LDL) and very low density lipoprotein (VLDL) binding to and degradation by fibroblast or HepG2 cells. Also provided are possible applications of the synthetic peptides in lowering human plasma LDL / VLDL cholesterol levels, thus inhibiting atherosclerosis. The present invention also relates to synthetic peptides that can improve HDL function and / or exert anti-inflammatory properties.

Description

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS[0001]This application is a continuation of and claims priority to U.S. patent application Ser. No. 12 / 675,073, which is national phase application of International Application No. PCT / US2008 / 074485, filed on Aug. 27, 2008, which claims priority to U.S. Provisional Patent Application No. 60 / 968,355, filed on Aug. 27, 2007, all of which are hereby incorporated herein by reference in their entirety.FIELD OF THE INVENTION[0002]This invention relates to the field of molecular biology and protein biology including polypeptides and polypeptide mimics. This application also relates to the field of cholesterol metabolism, catabolism, and the treatment and management of cholesterol associated disorders. The present invention also relates generally to the field of cardiovascular medicine. More specifically, the present invention relates to synthetic peptides that can rapidly lower plasma cholesterol through enhanced LDL and VLDL uptake and degrada...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/17A61P35/00A61K38/16
CPCA61K38/00C07K2319/03C07K14/775A61P1/04A61P11/06A61P13/12A61P15/00A61P15/10A61P17/00A61P17/04A61P17/06A61P19/02A61P19/10A61P21/04A61P25/00A61P25/16A61P25/28A61P27/02A61P31/04A61P31/10A61P31/12A61P33/00A61P35/00A61P3/06A61P37/06A61P37/08A61P5/00A61P7/00A61P7/06A61P9/00A61P9/10
Inventor ANANTHARAMAIAH, GATTADAHALLI M.GARBER, DAVID W.DATTA, GEETAHANDATTU, SHAILA P.MISHRA, VINOD K.
Owner UAB RES FOUND
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