on January 9, 2003
Published online before print January 9, 2003, doi: 10.1161/01.ATV.0000055741.13940.15
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Submitted on November 25, 2002
Accepted on December 20, 2002
A Synthetic Peptide That Inhibits Lipoprotein(a) Assembly
Rebecca J. Sharp ;
From the Department of Biochemistry (R.J.S., S.P.A.M.), University of Otago, Dunedin, New Zealand; Russell Grimwade School of Biochemistry and Molecular Biology (M.A.P.), University of Melbourne, Victoria, Australia; and Department of Medicine (S.M.M.), Northwest Lipid Research Laboratories, University of Washington, Seattle, Wash.
* To whom correspondence should be addressed. E-mail: sally.mccormick{at}stonebow.otago.ac.nz.
Objective--We previously reported that human apolipoprotein B100 (apoB) amino acids 4330-4397 were important for the initial noncovalent binding to apolipoprotein(a) [apo(a)] that facilitates lipoprotein(a) [Lp(a)] assembly. In this study, we aimed to additionally define the apoB sequences within the 4330-4397 region that were important for the noncovalent binding to apo(a).
Methods and Results--Alignment of the human apoB4330-4397 sequence with mouse apoB, which also noncovalently binds apo(a), revealed stretches of similar sequence, including a lysine-rich sequence spanning apoB amino acids 4372-4392. Structural analysis of the apoB4372-4392 sequence using the WHEEL program predicted an amphipathic 
-helix. Circular dichroism studies of a synthetic peptide spanning human apoB amino acids 4372-4392, both in the absence and presence of dimyristoylphosphatidylcholine, confirmed the -helical nature of the sequence. We tested the ability of the apoB4372-4392 peptide to bind to apo(a) and found that the peptide bound to apo(a) with high affinity but not to Lp(a). The apoB4372-4392 peptide inhibited Lp(a) assembly in Lp(a) formation assays far more effectively than the lysine analogue, 
-amino-n-caproic acid (IC50=40 µmol/L versus 10 mmol/L, respectively). Incorporation of the apoB4372-4392 peptide onto dimyristoylphosphatidylcholine vesicles yielded an even more effective inhibitor (IC50=4 µmol/L).
Conclusions--Our study shows that the apoB4372-4392 sequence mediates the initial noncovalent binding to apo(a) and has demonstrated that the apoB4372-4392 peptide is a novel and effective inhibitor of Lp(a) assembly.
Key words: lipoprotein(a) • assembly • apolipoprotein B • apolipoprotein(a) • peptide inhibitor
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