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

Journal of Lipid Research

卷:59

G.M. Anantharamaiah¹  Geeta Datta¹  Mayakonda N. Palgunachari¹  David W. Garber¹  Dennis Goldberg²  Eric Morrel²  C. Roger White³  Thomas C. Register⁴  Susan E. Appt⁴ 

[1] Department of Medicine, University of Alabama at Birmingham Medical Center, Birmingham, AL 35294;

[2] LipimetiX Development, Inc., Natick, MA 01760;

[3] To whom correspondence should be addressed.;

[4] Wake Forest School of Medicine, Winston-Salem, NC 27157;

关键词: peptides;    low density lipoprotein;    dyslipidemia;    lipoproteins;    apolipoprotein E;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown