A novel method for oral delivery of apolipoprotein mimetic peptides synthesized from all L-amino acids.
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.
Navab
Mohamad
M
Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1679, USA. mnavab@mednet.ucla.edu
Ruchala
Piotr
P
Waring
Alan J
AJ
Lehrer
Robert I
RI
Hama
Susan
S
Hough
Greg
G
Palgunachari
Mayakonda N
MN
Anantharamaiah
G M
GM
Fogelman
Alan M
AM
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000494:pharmacology; D000924:Anticholesteremic Agents / Q000494:pharmacology; D016632:Apolipoprotein A-I / Q000008:administration & dosage / Q000494:pharmacology; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000188:drug therapy; D001682:Biological Availability; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood; D008074:Lipoproteins / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018716:Molecular Mimicry; D009534:Niclosamide / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000494:pharmacology; D017035:Pravastatin / Q000494:pharmacology; D017433:Protein Structure, Secondary / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; C465468:D-4F peptide; C472885:L-4F peptide; D008074:Lipoproteins; D010455:Peptides; D009534:Niclosamide; D017035:Pravastatin