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Orally administered small peptides synergize statin activity

a statin activity and small peptide technology, applied in the field of atherosclerosis, can solve the problems of leading morbidity and mortality in cardiac disease, and achieve the effects of reducing mortality, reducing side effects, and reducing side effects

Inactive Publication Date: 2005-07-28
UNIV OF ALABAMA BIRMINGHAM RES FOUND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009] This invention provides novel peptides and amino acid pairs, administration of which mitigates one or more symptoms of atherosclerosis and other inflammatory conditions such as rheumatoid arthritis, lupus erythematous, polyarteritis nodosa, osteoporosis, Alzheimer's disease, congestive heart failure, endothelial dysfunction, viral illnesses such as influenza A, and diseases such as multiple sclerosis. In certain embodiments, it was a discovery of this invention that peptides comprising a class A amphipathic helix when formulated with “D” amino acid residue(s) and / or having protected amino and carboxyl termini can be orally administered to an organism, are readily taken up and delivered to the serum, and are effective to mitigate one or more symptoms of atherosclerosis. In certain embodiments, the peptides can be formulated with all “L” amino acid residues and are still effective, particular when administered by routes other than oral administration.
[0012] The peptides, and / or amino acid pairs, described herein are also effective for preventing the onset or inhibiting or eliminating one or more symptoms of osteoporosis.
[0013] It was also a surprising discovery that the peptides, and / or amino acid pairs, can be used to enhance (e.g., synergically enhance) the activity of statins and / or Ezetimibe or other cholesterol uptake inhibitors, thereby permitting the effective use of statins or cholesterol uptake inhibitors at lower dosages and / or cause the statins or cholesterol uptake inhibitors to be significantly more anti-inflammatory at any given dose.
[0068] The term “detoxify” when used with respect to lipids, LDL, or HDL refers the removal of some or all oxidizing lipids and / or oxidized lipids. Thus, for example, the uptake of all or some HPODE and / or HPETE (both hydroperoxides on fatty acids) will prevent or reduce entrance of these peroxides into LDLs and thus prevent or reduce LDL oxidation.

Problems solved by technology

Cardiovascular disease is a leading cause of morbidity and mortality, particularly in the United States and in Western European countries.

Method used

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  • Orally administered small peptides synergize statin activity
  • Orally administered small peptides synergize statin activity
  • Orally administered small peptides synergize statin activity

Examples

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example 1

Evaluation of Small Peptides to Mediate Symptoms of Atherosclerosis and Other Inflammatory Pathologies.

[0331] The apo A-I mimetic peptides described herein (see, e.g., Table 1) exhibit antiatherogenic properties similar to apo A-I in that they remove the “seeding molecules” (e.g., oxidized phospholipids such as Ox-PAPC, POVPC, PGPC, and PEIPC, etc.) necessary for artery wall cells to oxidized IDL and are similar to apo A-I in that they ameliorated atherosclerosis in mouse models.

[0332] The apo A-I mimetic peptides (e.g., D-4F, SEQ ID NO:8), differ from apo A-I in that they are also active in a co-incubation similar to apo J (see, e.g., U.S. Ser. No. 10 / 120,508 and PCT / US03 / 09988). These peptides generally do not have substantial sequence homology to apo A-I, but have homology in their helical structure and in their ability to bind lipids.

[0333] The smaller peptides described herein (see, e.g., Tables 4-7 herein) are similar to native apoA-I in that they prevent LDL oxidation and ...

example 2

Peptides Synergize Statin Activity

[0348]FIGS. 20 and 21 show the very dramatic synergy between a statin (pravastatin) and D-4F in ameliorating atherosclerosis in apoE null mice. Mice are known to be resistant to statins. The mice that received pravastatin in their drinking water at 20 μg / ml consumed a dose of pravastatin equal to 175 mg per day for a 70 Kg human and the mice that received pravastatin in their drinking water at 50 μg / ml consumed a dose of pravastatin equal to 437.5 mg per day for a 70 Kg human. As shown in FIGS. 20 and 21, these very high doses of pravastatin were not effective in ameliorating atherosclerotic lesions in apoE null mice. As shown in FIGS. 20 and 21, adding D-4F alone to the drinking water of the apoE null mice at concentrations of 2 μg / ml or 5 μg / ml did not reduce atherosclerotic lesions. These doses of D-4F would be equivalent to doses of 17.5 mg per day, and 43.75 mg per day, respectively, for a 70 Kg human. Remarkably, as shown in FIGS. 20 and 21, ...

example 3

Physical Properties of Novel Small Organic Molecules (Molecular Weight<900 Daltons) that Predict Ability to Render HDL More Anti-Inflammatory and Mitigate Atherosclerosis in a Mammal

[0350] It was a surprising finding of this invention that a number of physical properties predict the ability of the small peptides of this invention to render HDL more anti-inflammatory and to mitigate atherosclerosis and / or other pathologies characterized by an inflammatory response in a mammal. The physical properties include high solubility in ethyl acetate (e.g., greater than about 4 mg / mL), and solubility in aqueous buffer at pH 7.0. Upon contacting phospholipids such as 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC), in an aqueous environment, the particularly effective small peptides form particles with a diameter of approximately 7.5 nm (±0.1 nm), and / or form stacked bilayers with a bilayer dimension on the order of 3.4 to 4.1 nm with spacing between the bilayers in the stack of approximate...

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Abstract

This invention provides novel peptides that ameliorate one or more symptoms of atherosclerosis. The peptides are highly stable and readily administered via an oral route. The peptides are effective to stimulate the formation and cycling of pre-beta high density lipoprotein-like particles and / or to promote lipid transport and detoxification. This invention also provides a method of tracking a peptide in a mammal. In addition, the peptides inhibit osteoporosis. When administered with a statin, the peptides enhance the activity of the statin permitting the statin to be used at significantly lower dosages and / or cause the statins to be significantly more anti-inflammatory at any given dose.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation-in-part of U.S. Ser. No. 10 / 649,378, filed on Aug. 26, 2003, which claims benefit of and priority to U.S. Ser. No. 60 / 494,449, filed on Aug. 11, 2003, all of which are incorporated herein by reference in their entirety for all purposes.STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT [0002] This work was supported by United States Public Health Service and National Heart, Lung, and Blood Institute Grants HL30568 and HL34343. The Government of the United States of America may have certain rights in this invention.FIELD OF THE INVENTION [0003] This invention relates to the field of atherosclerosis. In particular, this invention pertains to the identification of a class of peptides that are orally administrable and that ameliorate one or more symptoms of atherosclerosis. BACKGROUND OF THE INVENTION [0004] Cardiovascular disease is a leading cause of morbidity an...

Claims

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Application Information

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IPC IPC(8): A61KA61K38/05A61K38/06C07K5/06C07K7/06
CPCA61K31/366A61K31/405C07K14/775C07K7/06C07K7/02C07K5/1021C07K5/1019C07K5/1016C07K5/101C07K5/0815C07K5/0812C07K5/0808A61K45/06A61K31/44A61K31/47A61K31/505A61K38/03A61K2300/00Y02P20/55A61P11/00A61P11/06A61P11/16A61P17/00A61P19/00A61P19/02A61P19/10A61P21/00A61P25/00A61P25/28A61P29/00A61P31/12A61P43/00A61P9/00A61P9/10A61P3/10A61K38/06
Inventor FOGELMAN, ALAN M.ANANTHARAMAIAH, GATTADAHALLI M.NAVAB, MOHAMAD
Owner UNIV OF ALABAMA BIRMINGHAM RES FOUND
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