Journal
AMINO ACIDS
Volume 43, Issue 6, Pages 2431-2441Publisher
SPRINGER WIEN
DOI: 10.1007/s00726-012-1322-y
Keywords
DhHP-6; ROS; N-methylated peptide; Permeability; Enzymatic stability
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Funding
- National Natural Science Foundation of China [30901863, 20872048]
- China Postdoctoral Science Foundation [20110491321]
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The deuterohemin-peptide conjugate, DhHP-6 (Dh-beta-AHTVEK-NH2), is a microperoxidase mimetic, which has demonstrated substantial benefits in vivo as a scavenger of reactive oxygen species (ROS). In this study, specific multi-site N-methylated derivatives of DhHP-6 were designed and synthesized to improve metabolic stability and intestinal absorption, which are important factors for oral delivery of therapeutic peptides and proteins. The DhHP-6 derivatives were tested for (1) scavenging potential of hydrogen peroxide (H2O2); (2) permeability across Caco-2 cell monolayers and everted gut sacs; and (3) enzymatic stability in serum and intestinal homogenate. The results indicated that the activities of the DhHP-6 derivatives were not influenced by N-methylation, and that tri-N-methylation of DhHP-6 could significantly increase intestinal flux, resulting in a two- to threefold higher apparent permeability coefficient. In addition, molecules with N-methylation at selected sites (e.g., Glu residue) showed high resistance against proteolytic degradation in both diluted serum and intestinal preparation, with 50- to 140-fold higher half-life values. These findings suggest that the DhHP-6 derivatives with appropriate N-methylation could retain activity levels equivalent to that of the parent peptide, while showing enhanced intestinal permeability and stability against enzymatic degradation. The tri-N-methylated peptide Dh-beta-AH(Me)T(Me)V(Me)EK-NH2 derived from this study may be developed as a promising candidate for oral administration.
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