A synthetic peptide that inhibits lipoprotein(a) assembly.
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).


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 alpha-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 alpha-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, epsilon-amino-n-caproic acid (IC50=40 micromol/L versus 10 mmol/L, respectively). Incorporation of the apoB4372-4392 peptide onto dimyristoylphosphatidylcholine vesicles yielded an even more effective inhibitor (IC50=4 micromol/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.
Sharp
Rebecca J
RJ
Department of Biochemistry, University of Otago, Dunedin, New Zealand.
Perugini
Matthew A
MA
Marcovina
Santica M
SM
McCormick
Sally P A
SP
D000595:Amino Acid Sequence; D000818:Animals; D001055:Apolipoproteins B / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002942:Circular Dichroism; D006801:Humans; D017270:Lipoprotein(a) / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D001055:Apolipoproteins B; D017270:Lipoprotein(a); D010446:Peptide Fragments; C472455:apoB 4372-4392, human