We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Improvement of enzymatic stability and intestinal permeability of deuterohemin-peptide conjugates by specific multi-site N-methylation.
- Authors
Dong, Qing-Guang; Zhang, Yong; Wang, Meng-Shu; Feng, Jiao; Zhang, Hai-Hong; Wu, Yong-Ge; Gu, Tie-Jun; Yu, Xiang-Hui; Jiang, Chun-Lai; Chen, Yan; Li, Wei; Kong, Wei
- Abstract
The deuterohemin-peptide conjugate, DhHP-6 (Dh-β-AHTVEK-NH), 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 (HO); (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-β-AH(Me)T(Me)V(Me)EK-NH derived from this study may be developed as a promising candidate for oral administration.
- Subjects
ENZYMATIC analysis; METHYLATION; PEROXIDASE; HYDROGEN peroxide; CHEMICAL stability; INTESTINAL absorption
- Publication
Amino Acids, 2012, Vol 43, Issue 6, p2431
- ISSN
0939-4451
- Publication type
Article
- DOI
10.1007/s00726-012-1322-y