Structure/function relationships of apolipoprotein a-I mimetic peptides: implications for antiatherogenic activities of high-density lipoprotein.
BACKGROUND
Apolipoprotein (apoA)-I mimetic peptides are a promising type of anti-atherosclerosis therapy, but how the structural features of these peptides relate to the multiple antiatherogenic functions of HDL is poorly understood.


OBJECTIVE
To establish structure/function relationships of apoA-I mimetic peptides with their antiatherogenic functions.


RESULTS
Twenty-two bihelical apoA-I mimetic peptides were investigated in vitro for the capacity and specificity of cholesterol efflux, inhibition of inflammatory response of monocytes and endothelial cells, and inhibition of low-density lipoprotein (LDL) oxidation. It was found that mean hydrophobicity, charge, size of hydrophobic face, and angle of the link between the helices are the major factors determining the efficiency and specificity of cholesterol efflux. The peptide with optimal parameters was more effective and specific toward cholesterol efflux than human apoA-I. Charge and size of hydrophobic face were also the major factors affecting antiinflammatory properties, and the presence of cysteine and histidine residues was the main factor determining antioxidant properties. There was no significant correlation between capacities of the peptides to support individual functions; each function had its own optimal set of features.


CONCLUSIONS
None of the peptides was equally effective in all the antiatherogenic functions tested, suggesting that different functions of HDL may have different mechanisms and different structural requirements. The results do suggest, however, that rationalizing the design of apoA-I mimetic peptides may improve their therapeutic value and may lead to a better understanding of mechanisms of various antiatherogenic functions of HDL.
D'Souza
Wilissa
W
Baker Heart and Diabetes Institute, PO Box 6492, St Kilda Rd, Melbourne 8008, Australia.
Stonik
John A
JA
Murphy
Andrew
A
Demosky
Steven J
SJ
Sethi
Amar A
AA
Moore
Xiao L
XL
Chin-Dusting
Jaye
J
Remaley
Alan T
AT
Sviridov
Dmitri
D
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D016632:Apolipoprotein A-I / Q000378:metabolism*; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D001692:Biological Transport; D002317:Cardiovascular Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D015195:Drug Design; D042783:Endothelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D018836:Inflammation Mediators / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D051379:Mice; D018716:Molecular Mimicry; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013499:Surface Properties
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D016632:Apolipoprotein A-I; D002317:Cardiovascular Agents; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; D010455:Peptides; C099252:oxidized low density lipoprotein; D002784:Cholesterol