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Structural requirements for antioxidative and anti-inflammatory properties of apolipoprotein A-I mimetic peptides

Department of Medicine, Biochemistry, and Molecular Genetics and Atherosclerosis Research Unit, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
The Journal of Lipid Research (Impact Factor: 4.73). 10/2007; 48(9):1915-23. DOI: 10.1194/jlr.R700010-JLR200
Source: PubMed

ABSTRACT Recently, attention has been focused on pharmacological treatments that increase HDL cholesterol to prevent coronary artery disease. Despite three decades of extensive research of human apolipoprotein A-I (apoA-I), the major protein component of HDL, the molecular basis for its antiatherogenic and anti-inflammatory functions remain elusive. Another protein component of HDL, apoA-II, has structural features similar to those of apoA-I but does not possess atheroprotective properties. To understand the molecular basis for the effectiveness of apoA-I, we used model synthetic peptides. We designed analogs of the class A amphipathic helical motif in apoA-I that is responsible for solubilizing phospholipids. None of these analogs has sequence homology to apoA-I, but all are similar in their lipid-associating structural motifs. Although all of these peptide analogs interact with phospholipids to form peptide:lipid complexes, the biological properties of these analogs are different. Physical-chemical and NMR studies of these peptides have enabled the delineation of structural requirements for atheroprotective and anti-inflammatory properties in these peptides. It has been shown that peptides that interact strongly with lipid acyl chains do not have antiatherogenic and anti-inflammatory properties. In contrast, peptides that associate close to the lipid head group (and hence do not interact strongly with the lipid acyl chain) are antiatherogenic and anti-inflammatory. Understanding the structure and function of apoA-I and HDL through studies of the amphipathic helix motif may lead to peptide-based therapies for inhibiting atherosclerosis and other related inflammatory lipid disorders.

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    • "The original concept that led to the development of an apoA-I mimetic peptide was based on the assumption that the functional properties of apoA-I, the predominant apolipoprotein of HDL, are derived from its secondary structure, a series of 22-mer amphipathic α-helices linked by proline residues [3]. A number of apoA-I mimetic peptides were developed comprising of one or two helices mimicking the secondary structure of apoA-I, without sharing homology with the primary sequence of apoA-I. "
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    • "APOA1 up-regulation is associated with breast and lung cancer as suggested elsewhere [62]. APOA1 is also linked to antioxidant function that is proposed to be involved in its vasculoprotective activity, apparently by complexing with paraoxonase [63]. Interestingly, studies provide new evidence supporting the notion that HDL plays a protective role in the lung. "
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    • "It is similar in sequence to the 18A peptide but contains 4 phenylalanine substitutions, and hence its name, in its hydrophobic face. Because of its relatively high hydrophobicity, the increase in phenylalanine content was found to increase the ability of this peptide to bind to oxidized lipids, a known anti-atherogenic function of HDL (Anantharamaiah et al., 2007). A version of the peptide when synthesized with d-amino acids called D-4F was found to be partially orally available and to reduce atherosclerosis in animal models (Navab et al., 2002). "
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