Myristyl

• Molecular Formula: CH3(CH2)12CO-hE18A-NH2
• Molecular Weight: 3805.67 g/mol
• Sequence: Myr-Leu-Arg-Arg-Leu-Arg-Arg-Arg-Leu-Leu-Arg-Asp-Trp-Leu-Lys-Ala-Phe-Tyr-Asp-Lys-Val- Ala-Glu-Lys-Leu-Lys-Glu-Ala-Phe-NH2

DESCRIPTION

The hepatic uptake of LDL is highly regulated. The LDL receptor (LDL-R) present on hepatocytes mediates the endocytosis of LDL and thus regulates the plasma level of the lipoprotein and cholesterol. In the acidic environment of the endosome, the LDL-R dissociates from its ligand and recycles back to the cell surface for further uptake of LDL. Apo E is an alternate ligand for the LDL-R and mediates the clearance of triglyceride-rich lipoproteins such as chylomicron remnants and VLDL (2). ApoE also binds to additional hepatic receptors such as LDL-R related protein (LRP) and heparan sulfate proteoglycans (HSPG). Like apoE, Ac-hE18A-NH2 and its variants can reduce plasma cholesterol and displays anti-inflammatory properties in model animals. Ac-hE18A-NH2 has already undergone phase 1 clinical trials as a lipid-lowering agent. In a recent study, the myristyl peptide variant of ApoE has been shown to reduce total and LDL cholesterol (even under severe dyslipidemic conditions) in apoE-null mice. As a result, it is though myristyl can act as an alternative to statins and HMG-CoA reductase inhibitors. Additionally, because of its enhanced potency at lower doses, myristyl has great therapeutic potential to lower cholesterol.

PROTOCOL

• Content & Potency: 5ml vial at 6mg/ml
• Suggested dosage: 100mcg/kg once weekly intravenously

CLINICAL RESEARCH

Novel Fatty Acyl ApoE Mimetic Peptides Have Increased Potency To Reduce Plasma Cholesterol In Mice And Macaques

Ac-hE18A-NH2 is a dual-domain apoE mimetic peptide that possesses the putative receptor binding domain from apoE (LRKLRKRLLR, denoted hE, residues 141 to 150) covalently attached to lipid-associating peptide 18A. Like apoE, Ac-hE18A-NH2 reduces plasma cholesterol in animal models and exhibits anti-inflammatory properties independent of its cholesterol-reducing effect. Ac-hE18A-NH2 has already undergone phase I clinical trials as a lipid-lowering agent. To explore the therapeutic potential, we designed and synthesized new analogs by linking ɑ -aminohexanoic acid, octanoic acid, or myristic acid to LRRLRRRLLR-18A-NH2 ([R]hE18A-NH2) and examined the cholesterol-lowering potency in animals.

The modified peptides effectively reduced plasma cholesterol in apoE-null mice fed standard chow or a Western diet; the myristyl analog was the most effective. A single administration of the myristyl analog reduced plasma total and LDL cholesterol in a dose-dependent manner in hypercholesterolemic cynomolgus macaques for up to 1 week despite continuation of a cholesterol-supplemented diet. The myristyl peptide (7.4 mg/kg) reduced total and LDL cholesterol at 24 hours by 64% and 74%, respectively; plasma HDL levels were modestly reduced and returned to baseline by the seventh day. These new analogs should exhibit enhanced potency at lower doses than Ac-hE18A-NH2, which may make them attractive therapeutic candidates for clinical trials.