Transport of Model Peptides across Isolated Cuticle of Ascaris suum: Influence of Methylation and Hydrogen Bonds
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The goal of this study was to delineate the factors which govern peptide transport across the cuticular/hypodermal complex of the parasitic nematode, Ascaris suum. Data obtained from this study are important to the successful development of peptidemimetic antiparasitic drugs to combat infection of livestock, thereby reducing parasite-related deaths and economic losses. We hypothesized that the permeability properties of the nematode cuticle would be similar to those obtained from previous studies with human intestinal cell model systems. A series of structurally-related model peptides was prepared from D-phenylalanine to study the influence of hydrogen bonding on permeability across isolated cuticle from A. suum. The amide nitrogens in the parent oligomer were sequentially methylated to give a series containing varying numbers of methyl groups. These peptides included AcfNH2, Acf(NMe- f)2NH2, and Ac(N-Me-f)3NHMe. The permeability properties of these peptides were studied using two-chamber diffusion cells and radiolabeled peptides. Rates of transport across the isolated cuticle for the three peptides were calculated from data collected from liquid scintillation and HPLC techniques. The results of these studies demonstrated a statistically significant increase in permeability coefficients across the cuticle with the addition of each methyl group. The peptide with three methyl groups and five hydrogen bonds, Ac(N-Me-f)3NHMe, had an experimentally calculated permeability coefficient of about 10-fold greater than the nonmethylated peptide, AcfNH2, which contained five hydrogen bonds. These results are in accordance with the hypothesis that a peptide must possess both an affinity for the aqueous-membrane interface and a reasonably low desolvation energy in order to efficiently traverse the cuticular/hypodermal complex in nematodes.