Site News  |   Monitor Keywords  |   Monitor Archive  |   Organizer  |   Account Info  |

Agent and compositions comprising the same for inhibiting lipases and phospholipases in body fluids, cells and tissues

Agent and compositions comprising the same for inhibiting lipases and phospholipases in body fluids, cells and tissues description/claims

(This invention claims priority from Provisional U.S. patent Application with Ser. No. 60/557,624 filed on 30th Mar. 2004)

The present invention relates to a protein and composition comprising the protein for inhibiting or reducing lipases and phospholipase enzymes in body fluids, cells, and tissues. The protein as described in the present invention and the composition comprising of the same are useful for the prevention or treatment of clinical manifestations and diseases caused as a consequence of lipase and phospholipase enzyme activities in the body fluids, cells, and tissues.

Lipases and phospholipases are key control elements in mammalian metabolism. They share many common features that set them apart from other metabolic enzyme classes, most importantly their association with “two-dimensional” substrates, i.e., lipid droplets, lipoproteins, phospholipid layers, biomembranes, and the resulting implications for their cleavage mechanism and regulation.

The pancreatic lipase (PL) is believed to be effective in causing a partial hydrolysis of triglycerides to obtain fatty acids and monoglycerides that, together with the bile acids, form complexes, which are then absorbed through the intestinal mucosa. Hepatic lipase (HL) and lipoprotein lipase (LPL) are the two major lipolytic enzymes responsible for the hydrolysis of triglycerides and phospholipids present in circulating plasma lipoproteins. Both lipases are attached to the vascular endothelium via cell surface proteoglycans. HL is primarily involved in the metabolism of chylomicron remnants, intermediate density lipoproteins, and high-density lipoproteins, whereas LPL catalyzes the hydrolysis of triglycerides from chylomicrons and very low-density lipoproteins. In addition to their traditional function as lipolytic enzymes, HL and LPL appear to serve as ligands that mediate the interaction of lipoproteins to cell surface receptors and/or proteoglycans.

Accumulation and distribution of triglyceride-rich lipoprotein-associated fatty acids at extra-hepatic sites is facilitated by LPL. The enzyme is also involved in several non-lipolysis associated functions, including the cellular uptake of whole lipoprotein particles and lipophilic vitamins. The tissue-specific variations of LPL expression have been implicated in the pathogenesis of various lipid disorders, obesity, and atherosclerosis. LPL expressed by cells of the vascular wall, particularly macrophages, have identified additional actions of the enzyme that contribute to the promotion of foam cell formation and atherosclerosis. Development of drugs specifically acting on the cholesteryl ester transfer protein and lipoprotein lipase systems, are being explored.

Over the past several years significant advances have been made in our understanding of new, alternative mechanisms by which HL and LPL modulate lipoprotein metabolism and the development of atherosclerosis in vivo. Advances have also been made in our understanding of the intravascular metabolism of triglyceride-rich lipoproteins. It is now known that the complex extracellular interactions of triglyceride-rich lipoprotein-associated apolipoprotein E, lipoprotein lipase, and hepatic lipase with heparan sulfate proteoglycans and lipoprotein receptors facilitate the hepatocellular uptake of triglyceride-rich lipoproteins. Recent studies have also revealed that the intracellular fate of internalized triglyceride-rich lipoproteins is highly complex. The dissociation of triglyceride-rich lipoprotein components within intracellular endosomal compartments involves the recycling of apolipoprotein E, whereas the remaining lipid core associated with apolipoprotein B is susceptible to lysosomal degradation.

The high incidence of atherosclerosis in diabetic patients has been correlated with LPL activity in macrophages. Accumulating evidence indicates that LPL produced by macrophages in the vascular wall may favor the development of atherosclerosis by promoting lipid accumulation within the lesion.

The potential of lipases as drug targets for the treatment of metabolic syndrome and cardiovascular disorders is increasingly recognized. It is now believed that the front line therapy for diseases related to lipid absorption and metabolism should be to inhibit or reduce lipase activity in the body fluids, cells, and tissues.

Lipase inhibitors have been reported from various natural products, especially from microbial sources. The example of such inhibitors include lipstatin and Panclicins A-E from Streptomyces species or their synthetic derivatives that inhibit the hydrolysis of triglycerides and cholesterol esters (Hochuli et al., Lipstatin, and Inhibitor of Pancreatic Lipase, Produced by Streptornyces Toxytricini, II. Chemistry and Structure Elucidation, J. Antibiot. (Tokyo), 1987 August, 40(8):1086-91; Fernandez et al., Effects of Tetrahydrolipstatin, a Lipase Inhibitor, on Absorption of Fat from the Intestine of the Rat, Biochim. Biophys. Acta., 1989 February, 20, 1001(3):249-55; Yoshinari et al, Panclicins, Novel Pancreatic Lipase Inhibitors, II. Structural elucidation, J. Antibiot. (Tokyo), 1994 December, 47(12):1376-84) and is being used for treatment of obesity (U.S. Pat. No. 5,540,917). Besides, a number of molecules have been identified from plant sources including tannins isolated from Cassia nomame (U.S. Pat. No. 5,629,338). LPL has been shown to be involved in the pathogenesis of atherosclerosis (Mead et al, Lipoprotein Lipase, a Key Role in Atherosclerosis?, FEBS Lett., 1999 November, 26, 462(1-2):1-6). Inhibition of LPL is believed to prevent the atherosclerotic process (Zimmerman et al., Lipoprotein Lipase Mediates the Uptake of Glycated LDL in Fibroblasts, Endothelial Cells, and Macrophages, Diabetes, 50, 1643-1653, 2001).

Phospholipases specifically act on and hydrolyse membrane phospholipids and generate mediators implicated in signal transduction and inflammatory processes. The role of phospholipase A2 (PLA2) is well known in the generation of arachidonic acid, which is responsible for leukotriene and prostaglandin synthesis; PLA2 inhibitors have been proposed as drugs for variety of inflammatory and degenerative diseases. Lipoprotein-associated phospholipase A2 has been shown to be involved in atherosclerosis and its inhibition is being proposed for its treatment (Leach et al., Lipoprotein-Associated PLA2 Inhibition—A Novel, Non-Lipid Lowering Strategy for Atherosclerosis Therapy, Farmaco, 2001 January-February, 56(1-2):45-50).

The present invention relates to a protein and composition comprising the same for inhibiting or reducing lipases and phospholipase enzymes in body fluids, cells, and tissues. The protein as described in the present invention and the composition comprising of the same are useful for the prevention or treatment of clinical manifestations and diseases caused as a consequence of lipase and phospholipase enzyme activities in the body fluids, cells, and tissues.

In the preferred embodiments the protein having lipase inhibitory activity can be synthesized, produced by recombinant technology or isolated from natural sources.

In the most preferred embodiments the protein is isolated from the seeds of plant species belonging to Moringa genus.

In the preferred embodiments the compositions for inhibition of lipases or phospholipases comprises of protein as described in the present invention in a therapeutically effective amount and pharmaceutically inert adjuvants, diluents or carriers.

In the preferred embodiments the compositions for inhibition of lipases or phospholipases comprising of protein as described in the present invention may also be combined with other active ingredients.

The protein as described in the present invention or composition comprising the same is believed to have the ability to inhibit lipases and phospholipases under physiological conditions, and thereby would have corresponding effectiveness for prevention or treatment of metabolic syndrome, cardiovascular disorders, and inflammatory diseases.

In the preferred embodiments the protein as described in the present invention or the compositions comprising proteins are useful as for inhibition of lipases and phospholipases in the body fluids, cells, and tissues for the prevention and treatment of metabolic syndrome, cardiovascular disorders, and inflammatory diseases.

In another embodiments, the protein as described in the present invention or the composition comprising a protein can be used for prevention or treatment of metabolic disorders like obesity, diabetes, and atherosclerosis.

• Provisional Patent
• Utility Patent

• What Is a Patent?
• What Is a Trademark or Servicemark?
• What Is a Copyright?
• Patent Laws