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.
Highlights
Administered subcutaneously, D-4F or L-4F are efficacious, but only D-4F is orally efficacious because of digestion of L-4F by gut proteases
We previously reported that a class G* amphipathic peptide taken from the sequence of apo J and synthesized from all D-amino acids (D-[113-122]apoJ) had biologic activity after oral administration similar to D-4F (5)
Preliminary molecular modeling suggests that resistance to the action of trypsin maybe due to niclosamide surrounding L-4F in the complex, protecting the peptide from the action of trypsin, which acts at the C terminus of lysine and arginine residues
Summary
Administered subcutaneously, D-4F or L-4F are efficacious, but only D-4F is orally efficacious because of digestion of L-4F by gut proteases. A novel method for oral delivery of apolipoprotein mimetic peptides synthesized from all L-amino acids. L-amino acids and administered orally to mice, it was ineffective in improving lipoprotein inflammatory properties (1). When the peptide was synthesized from all D-amino acids and administered orally, lipoprotein inflammatory properties were improved and lesions were decreased in these mouse models of atherosclerosis (1). It appeared likely that D-4F and L-4F only differed in their ability to resist enzymatic degradation after oral administration. Based on the work of Garber et al (3), we would predict that resistance to enzymatic degradation would be an advantage for oral administration of a peptide synthesized from D-amino acids, but after absorption by any route, it would likely remain undegraded in tissues for prolonged periods.
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