Compositions and Methods for Treating Atherosclerosis

Abstract

Reverse peptides and mimetics of a mammalian serum amyloid A isoform 2.1 (SAA2.1) domain or a portion thereof and compositions and pharmaceutical compositions thereof are provided that enhance the effect on macrophage cholesterol ester hydrolase activity. Methods of using these reverse peptides, mimetics thereof and compositions in the treatment and / or prevention of atherosclerosis as well as coronary heart disease and cardiovascular disease are also provided.

Description

[0001]This patent application is a continuation of U.S. Ser. No. 11 / 693,820 filed Mar. 30, 2007, which claims the benefit of priority from U.S. Provisional Application Ser. No. 60 / 788,516, filed Mar. 31, 2006, teachings each of which are herein incorporated by reference in their entireties.FIELD OF THE INVENTION [0002]The present invention relates to synthetic reverse peptides of a macrophage cholesterol ester hydrolase enhancing domain of mammalian serum amyloid A isoforms 2.1 (SAA2.1) and 1.1 (SAA1.1) or a portion thereof. These reverse peptides, mimetics thereof or compositions containing these reverse peptides or mimetics thereof, and pharmaceutical compositions comprising one or more of these reverse peptides, mimetics thereof or compositions, are useful in inhibiting the storage of cholesterol and potentiating the mobilization and release of cholesterol from inflammatory or atherosclerotic sites in a subject. The reverse peptides and mimetics thereof, and the compositions and ...

AI Technical Summary

Benefits of technology

[0006]A selected peptide domain of mammalian serum amyloid A isoforms 2.1 (SAA2.1) and 1.1 (SAA1.1) and portions thereof and mimetics thereof have been demonstrated to have a potent enhancing effect on macrophage cholesterol ester hydrolase (CEH) activity. As shown herein, reverse peptides of this domain, or a portion thereof, also have a potent enhancing effect on CEH activity. Reverse peptides of this domain or a portion thereof shift macrophage cholesterol into a transportable form that is then rapidly exported from the cell in the presence of a cholesterol transporter and a cholesterol acceptor, high density lipoprotein (HDL). Thus, these reverse peptides and mimetics thereof, more preferably retro-inversal D amino acid peptides and mimetics thereof, are useful in methods of inhibiting the storage of cholesterol and potentiating the mobilization and release of cholesterol from inflammatory or atherosclerotic sites in a subject. Further, these reverse peptides and mimetics thereof, more preferably retro-inversal D amino acid peptides and mimetics thereof, are effective at regressing and / or decreasing formation of arterial atherosclerotic lesions and treating or preventing atherosclerosis, cardiovascular disease, coronary heart disease and inflammation in a subject.

[0010]Another aspect of the present invention relates to compositions with a formula of Y-Z or Q-Y-Z, wherein Y comprises a reverse peptide or mimetic thereof of the present invention with CEH enhancing activity; Z comprises a compound linked to Y that enhances the performance of Y; and in embodiments comprising Q, Q comprises another compound linked to Y-Z which enhances performance of the Q-Y-Z composition. Q may be identical to Z or different from Z. Exemplary Z or Q compounds include, but are not limited to a targeting agent, a second agent for treatment of atherosclerosis, cardiovascular disease or coronary heart disease, an agent which enhances solubility, absorption, distribution, half-life, bioavailability, stability, activity and / or efficacy, and an agent which reduces toxicity or side effects of the composition. Exemplary targeting agents of Z and / or Q include macrophage targeting agents such as, for example, a liposome, a microsphere, a ligand for a SAA receptor, hepatic targeting agents, antibodies and active fragments thereof such as, for example, Fab fragments, and additional agents specific to atherosclerotic plaques and / or inflammatory sites.

[0011]Another aspect of the present invention relates to pharmaceutical compositions comprising a reverse peptide, peptide variant, a mimetic thereof, or a Y-Z or Q-Y-Z composition which enhances CEH activity. Pharmaceutical compositions of the present invention further comprise a vehicle that is pharmaceutically suitable for in vivo administration. In one embodiment, the reverse peptide, mimetic thereof or the composition is complexed with a lipid. A phospholipid vesicle which encapsulates the reverse peptide, the mimetic thereof or the composition can also be used. In other embodiments, vehicles suitable for pharmaceutical administration in vivo may comprise aqueous solutions including, but not limited to, phosphate buffered saline or phosphate buffered saline containing glucose, preferably 0.01 to 10% weight / volume glucose, more preferably 5% weight / volume glucose.

Problems solved by technology

However, reverse peptides do not always exhibit similar efficacy to their corresponding forward peptide.

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