Growth hormone-releasing peptides as negative modulators of...

A - Human Necessities – 61 – K

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A61K 38/27 (2006.01) A61K 38/25 (2006.01) A61P 9/10 (2006.01) C07K 14/61 (2006.01)

Patent

CA 2399548

Growth hormone releasing peptides (GHRPs), a family of synthetic analogs modelled from Met-enkephalin, have been found to bind a novel class of specific GHRP receptors in the mammalian heart that are distinct from the pituitary GHRP receptors involved in GH secretion. CD36, a multifunctional B-type scavenger receptor, has been identified as the unique GHRP binding site in the heart. CD36 mediates the uptake of lipoproteins into a number of cell types and was recognized to play a crucial role in scavenging oxidized low density lipoproteins in monocyte/ macrophages leading to foam cell formation, a key step in fatty streaks formation. The hexapeptide GHRP prototypes hexarelin (His - DMe - Trp - Ala - Trp - D Phe - Lys - NH2) and EP 80317 (Haic-D Me - Trp -D Lys - Trp - D Phe- Lys - NH2), the latter analog being devoid of GH-secreting activity in vivo, have been shown to reduce fatty streak lesions and hypercholesterolemia in apolipoprotein E (Apo E) null mice fed a high fat high cholesterol diet (HFHC). In addition, non-HDL cholesterol was significantly decreased, whereas HDL cholesterol tended to increase. GHRP treatment also inhibited oxLDL-induced monocyte chemotaxis in the peritoneal cavity, which was associated with a reduced expression of the CD36 protein on peritoneal monocytes/macrophages. GHRPs may represent a novel therapeutic avenue to reduce the severe morbidity associated with the arterial disease atherosclerosis and its complications, such as myocardial infarction and strokes, that occur despite current management strategies.

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