Novel fatty acyl apoE mimetic peptides have increased potency to reduce plasma cholesterol in mice and macaques

Abstract

Ac-hE18A-NH2 is a dual-domain apoE mimetic peptide that possesses the putative receptor binding domain from apoE (LRKLRKRLLR, denoted hE; residues 141–150) 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 more, we designed and synthesized new analogues 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 analogue was the most effective. A single administration of the myristyl analogue reduced plasma total and LDL cholesterol in a dose-dependent manner in hypercholesterolemic cynomolgus macaques for up to 1 week despite the continuation of a cholesterol-supplemented diet. The myristyl peptide (7.4 mg/kg) reduced total and LDL cholesterol at 24 h by 64% and 74%, respectively; plasma HDL levels were modestly reduced and returned to baseline by day 7. These new analogues should exhibit enhanced potency at lower doses than Ac-hE18A-NH2, which may make them attractive therapeutic candidates for clinical trials.

Apolipoprotein Mimetic Peptides: Potential New Therapies for Cardiovascular Diseases

“…As for apoE mimetic peptides, their main target is for lowering LDL-C, a well-established therapeutic strategy that has proven to be successful for many other types of approved drugs like statins and proprotein convertase subtilisin/kexin type 9 (PCSK9)-inhibitors [ 96 , 110 ]. However, even if these peptides efficiently lower plasma LDL-C, there is still some uncertainty about the fate of the LDL particles lowered by these peptides.…”

“…This peptide called Ac-[R]hE18A-NH2 ( Table 4 ) was even more potent in increasing lipoprotein uptake in cell culture studies [ 87 ]. Derivatives of Ac-[R]hE18A-NH2 containing α-aminohexanoic acid or other fatty acids (octanoic or myristic acid) attached to the N-terminus have also been described [ 96 ]. It was hypothesized that making these peptides more hydrophobic will enhance their ability to bind to atherogenic apoB-containing lipoproteins.…”

“…It was hypothesized that making these peptides more hydrophobic will enhance their ability to bind to atherogenic apoB-containing lipoproteins. The Myr-[R]hE18A-NH2 peptide ( Table 4 ), containing myristic acid, was almost two-times more effective than Ac-hE18A-NH2 peptide in decreasing plasma cholesterol in apoE-null mice [ 96 ]. It also significantly reduced total and LDL-cholesterol (LDL-C) at lower doses than Ac-hE18A-NH2 in hypercholesterolemic cynomolgus macaques [ 96 ].…”

“…The Myr-[R]hE18A-NH2 peptide ( Table 4 ), containing myristic acid, was almost two-times more effective than Ac-hE18A-NH2 peptide in decreasing plasma cholesterol in apoE-null mice [ 96 ]. It also significantly reduced total and LDL-cholesterol (LDL-C) at lower doses than Ac-hE18A-NH2 in hypercholesterolemic cynomolgus macaques [ 96 ]. LDL-C was reduced by approximately 75% after 24 h and remained decreased for at least 3 days.…”

Identification of a novel cholesterol-lowering dipeptide, phenylalanine-proline (FP), and its down-regulation of intestinal ABCA1 in hypercholesterolemic rats and Caco-2 cells

“…While, apoE mimetic peptides have increased potency to reduce plasma cholesterol through the changes of electrophoretic mobility of LDL particle in mice 32 . We tried to experimentally evaluate the effect of FP on the electrophoretic mobility of LDL particle in vitro .…”