期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 18, 期 24, 页码 8669-8678出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2010.09.074
关键词
Peptide mimetics; ApoA-I; HDL (high density lipoproteins); Pre-beta HDL; Atherosclerosis
Reverse cholesterol transport promoted by HDL-apoA-I is an important mechanism of protection against atherosclerosis. We have previously identified apoA-I mimetic peptides by synthesizing analogs of the 22 amino acid apoA-I consensus sequence (apoA-I-cons) containing non-natural aliphatic amino acids. Here we examined the effect of different aliphatic non-natural amino acids on the structure-activity relationship (SAR) of apoA-I mimetic peptides. These novel apoA-I mimetics, with long hydrocarbon chain (C5-8) amino acids incorporated in the amphipathic alpha helix of the apoA-I-cons, have the following properties: (i) they stimulate in vitro cholesterol efflux from macrophages via ABCA1; (ii) they associate with HDL and cause formation of pre-beta HDL particles when incubated with human and mouse plasma; (iii) they associate with HDL and induce pre-beta HDL formation in vivo, with a corresponding increase in ABCA1-dependent cholesterol efflux capacity ex vivo; (iv) at high dose they associate with VLDL and induce hypertriglyceridemia in mice. These results suggest our peptide design confers activities that are potentially anti-atherogenic. However a dosing regimen which maximizes their therapeutic properties while minimizing adverse effects needs to be established. (C) 2010 Elsevier Ltd. All rights reserved.
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