Structural features of apolipoprotein B synthetic peptides that inhibit lipoprotein(a) assembly.

Journal of Lipid Research
Rebecca J SharpSally P A McCormick

Abstract

Lipoprotein(a) [Lp(a)] is assembled via an initial noncovalent interaction between apolipoprotein B100 (apoB) and apolipoprotein(a) [apo(a)] that facilitates the formation of a disulfide bond between the two proteins. We previously reported that a lysine-rich, alpha-helical peptide spanning human apoB amino acids 4372-4392 was an effective inhibitor of Lp(a) assembly in vitro. To identify the important structural features required for inhibitory action, new variants of the apoB4372-4392 peptide were investigated. Introduction of a central leucine to proline substitution abolished the alpha-helical structure of the peptide and disrupted apo(a) binding and inhibition of Lp(a) formation. Substitution of hydrophobic residues in the apoB4372-4392 peptide disrupted apo(a) binding and inhibition of Lp(a) assembly without disrupting the alpha-helical structure. Substitution of all four lysine residues in the peptide with arginine decreased the IC50 from 40 microM to 5 microM . Complexing of the arginine-substituted peptide to dimyristoylphosphatidylcholine improved its activity further, yielding an IC50 of 1 microM. We conclude that the alpha-helical structure of apoB4372-4392, in combination with hydrophobic residues at the lipid/wate...Continue Reading

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Citations

May 19, 2010·American Journal of Therapeutics·Valmore BermúdezManuel Velasco
Oct 9, 2012·Metabolism: Clinical and Experimental·Jane Hoover-Plow, Menggui Huang
Dec 21, 2005·Journal of Cellular and Molecular Medicine·Harjot K SainiNaranjan S Dhalla
May 19, 2009·Atherosclerosis·S CharrièreC Marçais

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