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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:502.)
© 2003 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

A Synthetic Peptide That Inhibits Lipoprotein(a) Assembly

Rebecca J. Sharp; Matthew A. Perugini; Santica M. Marcovina; Sally P.A. McCormick

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.

Correspondence to Dr Sally McCormick, Biochemistry Department, University of Otago, 710 Cumberland St, PO Box 56, Dunedin, New Zealand. 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 further 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 apoB_4372–4392 peptide to bind to apo(a) and found that the peptide bound to apo(a) with high affinity but not to Lp(a). The apoB_4372–4392 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 apoB_4372–4392 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 apoB_4372–4392 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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