Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1994-12-23
1998-03-31
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 12, 514 21, 530324, 530326, 530359, G01N 3353, A61K 3800
Patent
active
057338795
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to new peptides and new proteins, to a process for their preparation, and to their use as cholesterol acceptors.
Atherosclerosis, and its attendant complications such as coronary heart disease in particular are among the most common and critical health problems today. A number of risk factors have been implicated in the development of "premature" atherosclerosis, one of the most important of these being elevated plasma cholesterol. Because of the crucial role that cholesterol appears to play in the occurrence of heart disease, a great deal of attention has been devoted to the study of its metabolism in the human body.
The major function of the apolipoproteins is to carry lipids including cholesterol, phospholipids and triglycerides in plasma and to deliver these lipids to a variety of cells (Pownall et al., 1987; Kovanen et al., 1990). These lipid-apolipoprotein complexes constitute the different classes of the plasma lipoproteins. Most of the smaller water-soluble apolipoproteins have a high alpha-helical content, and contain several amphipathic segments with a high degree of homology (De Loof et al., 1987; Brasseur et al., 1990). Low density lipoproteins are involved in the delivery of cholesterol to peripheral cells (Brown et al., 1986; Gianturco et al., 1987), while high density lipoproteins (HDL) are responsible for the transport of excess cholesterol from the peripheral tissues to the liver, i.e., "reverse cholesterol transport". Several mechanisms have been proposed to account for the targeting of the HDL to the liver. These include the uptake of apoE-rich HDL1, the direct uptake of HDL2 after the enzymatic action of hepatic lipase on HDL3, and the transfer of cholesteryl esters from HDL2 to apoB containing lipoproteins under the action of the cholesteryl ester transfer protein (CETP). Lecithin cholesterol acyl transferase (LCAT) and lipoprotein lipase (LPL) are enzymes which play major roles in the conversion of the nascent discoidal HDL and of the small HDL3 particles, which act as acceptors of cholesterol from peripheral cells, into larger HDL2 particles (Phillips et al., 1987). These are further catabolized, thus directing the flux of cholesterol to the liver. It has now been well documented (Delamatre et al., 1986) that apo AI, representing the major apoprotein constituent of HDL, is the major apoprotein involved in these processes.
Synthetic peptides, mostly 18-22 residues long, have been used as models for the study of helix-lipid interactions in an apolipophospholipid-protein complex (Sparrow and Gotto, 1981). The sequences of these amphipathic peptides either matched those of the helices of apo AI, AII or E (Fukushima et al., 1980) or represented consensus sequences for the various helical repeats identified in apo AI (Pownall et al., 1980; Anantharamaiah, 1986). The properties of these peptides and of the lipid-peptide complexes have been extensively studied and compared with those of the native apolipoproteins (Segrest et al., 1983; Segrest et al., 1990).
The differences observed between the lipid-binding and LCAT activation properties of the synthetic 18-residue peptides and those of the native apolipoproteins were attributed to the lack of cooperativity between single peptides in the lipid-peptide complexes (Fukushima et al., 1980).
The following sequence: (Anantharamaiah, 1986; Segrest et al., 1990).
Although this peptide is an amphipathic lipid-associating peptide, nothing is demonstrated in the above-mentioned article with regard to a capacity of promoting cholesterol efflux from lipid-loaded cells. Epand et al. (1989) have described the LCAT activation and vesicle lysing properties of the peptide of formula:.
The aim of the invention is to provide new peptides and proteins and phospholipid complexes thereof acting as acceptors and carriers for excess cholesterol.
The aim of the invention is also to provide new peptides and proteins and phospholipid complexes thereof which combine a maximal storage capacity for cholesterol and an optimal substrate effici
REFERENCES:
patent: 5177189 (1993-01-01), Dyer et al.
patent: 5182364 (1993-01-01), Dyer et al.
Epand et al. J. Biol. Chem, vol. 264:8, Mar. 1989, pp. 4628-4635.
Brasseur et al. J. Biol. Chem., vol. 266: 24, 25, Aug. 1991, pp. 16120-16127.
Journal of Biological Chemistry, vol. 264, No. 8, 15 Mar. 1989, Baltimore, U.S., pp. 4628-4635, Epand et al, `Properties of lipid complexes with amphipatic helix-forming peptides` cited in the application.
Journal of Biological Chemistry, vol. 266, No. 24,25 Aug. 1991, pp. 16120-16127, Brasseur `Differentiation of lipid-associating helices by use of three-dimensional molecular hydrophobicity et al`.
Srinivas RV, et al. Journal of Cellular Biochemistry 45:224-237 (1991) "Inhibition of Virus-Induced Cell Fusion by Apolipoprotein A-I and its Amphipathic Peptide Analogs".
Jorgensen EV et al. The Journal of Biological Chemistry, 264 (16) 9215-9219 (1989) "Synthetic Amphipathic Peptides Resembling Apolipoproteins Stimulate Release of Human Placental Lactogen".
Epand RM et al. The Journal of Biological Chemistry 262(19) 9389-9396 (1987) "Studies of Synthetic Peptide Analogs of the Amphipathic Helix".
Brasseur Robert
Deleys Robert
Labeur Christine
Rosseneu Maryvonne
N.V. Innogenetics S.A.
Touzeau Lynn
Tsang Cecilia J.
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