Structural requirements for antioxidative and anti-inflammatory properties of apolipoprotein A-I mimetic peptides.
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.
Anantharamaiah
G M
GM
Department of Medicine, Biochemistry, and Molecular Genetics and Atherosclerosis Research Unit, University of Alabama at Birmingham, Birmingham, AL 35294, USA. ananth@uab.edu
Mishra
Vinod K
VK
Garber
David W
DW
Datta
Geeta
G
Handattu
Shaila P
SP
Palgunachari
Mayakonda N
MN
Chaddha
Manjula
M
Navab
Mohamad
M
Reddy
Srinivasa T
ST
Segrest
Jere P
JP
Fogelman
Alan M
AM
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000975:Antioxidants / Q000627:therapeutic use*; D016632:Apolipoprotein A-I / Q000737:chemistry / Q000627:therapeutic use*; D001054:Apolipoproteins A / Q000627:therapeutic use*; D050197:Atherosclerosis / Q000188:drug therapy; D040761:Biomimetic Materials / Q000627:therapeutic use; D008076:Cholesterol, HDL / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D016632:Apolipoprotein A-I; D001054:Apolipoproteins A; D008076:Cholesterol, HDL