A novel method for oral delivery of apolipoprotein mimetic peptides synthesized from all L-amino acids.

Academic Article

Abstract

  • Administered subcutaneously, D-4F or L-4F are equally efficacious, but only D-4F is orally efficacious because of digestion of L-4F by gut proteases. Orally administering niclosamide (a chlorinated salicylanilide used as a molluscicide, antihelminthic, and lampricide) in temporal proximity to oral L-4F (but not niclosamide alone) in apoE null mice resulted in significant improvement (P < 0.001) in the HDL-inflammatory index (HII), which measures the ability of HDL to inhibit LDL-induced monocyte chemotactic activity in endothelial cell cultures. Oral administration of L-[113-122]apoJ with niclosamide also resulted in significant improvement (P < 0.001) in HII. Oral administration of niclosamide and L-4F together with pravastatin to female apoE null mice at 9.5 months of age for six months significantly reduced aortic sinus lesion area (P = 0.02), en face lesion area (P = 0.033), and macrophage lesion area (P = 0.02) compared with pretreatment, indicating lesion regression. In contrast, lesions were significantly larger in mice receiving only niclosamide and pravastatin or L-4F and pravastatin (P < 0.001). In vitro niclosamide and L-4F tightly associated rendering the peptide resistant to trypsin digestion. Niclosamide itself did not inhibit trypsin activity. The combination of niclosamide with apolipoprotein mimetic peptides appears to be a promising method for oral delivery of these peptides.
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    Keywords

  • Administration, Oral, Animals, Anti-Inflammatory Agents, Non-Steroidal, Anticholesteremic Agents, Apolipoprotein A-I, Apolipoproteins E, Atherosclerosis, Biological Availability, Female, Humans, Inflammation, Lipoproteins, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Mimicry, Niclosamide, Peptides, Pravastatin, Protein Structure, Secondary
  • Digital Object Identifier (doi)

    Authorlist

  • Navab M; Ruchala P; Waring AJ; Lehrer RI; Hama S; Hough G; Palgunachari MN; Anantharamaiah GM; Fogelman AM
  • Start Page

  • 1538
  • End Page

  • 1547
  • Volume

  • 50
  • Issue

  • 8