ApoA-I mimetic peptides promote pre-ß HDL formation in vivo causing remodeling of HDL and triglyceride accumulation at higher dose.
Bioorg Med Chem
; 18(24): 8669-78, 2010 Dec 15.
Article
in En
| MEDLINE
| ID: mdl-21115285
ABSTRACT
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 (C(5-8)) amino acids incorporated in the amphipathic α 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-ß HDL particles when incubated with human and mouse plasma; (iii) they associate with HDL and induce pre-ß 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Peptide Fragments
/
Triglycerides
/
Apolipoprotein A-I
/
High-Density Lipoproteins, Pre-beta
/
Lipoproteins, HDL
Limits:
Animals
/
Humans
Language:
En
Journal:
Bioorg Med Chem
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2010
Document type:
Article
Affiliation country:
United States