Abstract

Apolipoprotein(apo) E is a ligand for clearance of lipoprotein remnants such as chylomicorons and very low density lipoproteins (VLDL). It has anti-atherogenic and anti-inflammatory properties. Therefore there is extensive research ongoing to create peptides that can mimic properties of apoE. A number of synthetic peptides that encompass different regions of apoE have been studied for inhibiting inflammatory states including Alzheimar’s disease.  We describe the design and studies of a dual-domain apoE mimetic peptide, Ac-hE18A-NH2. This peptide consists of 141-150 putative receptor binding region of human apoE covalently linked to a well characterized class A amphipathic helix, 18A, which has no sequence homology to any other exchangeable apolipoprotein sequences. It demonstrates dramatic effects in reducing plasma cholesterol in dyslipidemic mouse and rabbit and Monkey, including sustained effect in monkeys. Analogous to apoE, this peptide bypasses LDL receptor for the hepatic uptake of atherogenic lipoproteins via heparin sulphate proteoglycans (HSPG).  ApoE mimetics such as Ac-hE18A-NH2 may therefore restore or replace ligand in genetically induced hyperlipidemias to enable reduction in atherogenic lipoproteins via HSPG even in the absence of functional LDL receptors. Therefore this and similar peptides may be useful in the treatment of a dyslipidemic disorders such as familial hyperlipidemia and atherosclerosis. Phase 1 clinical studies in patients with risk for atherosclerosis has shown encouraging results.