The DOI matches its Crossref record; 35 of the 35 references it cites were found in a registry or an index.
Improvement of enzymatic stability and intestinal permeability of deuterohemin-peptide conjugates by specific multi-site N-methylation
Abstract
The deuterohemin-peptide conjugate, DhHP-6 (Dh-β-AHTVEK-NH(2)), 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 (H(2)O(2)); (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(2) derived from this study may be developed as a promising candidate for oral administration.
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Cited by
Sun, M., Hu, H., Sun, L., & Fan, Z. (2020) · Chinese Chemical Letters · doi:10.1016/j.cclet.2020.02.035 · Cited by 50
Metadata
- Authors
- Dong, Q.-G., Zhang, Y., Wang, M.-S., Feng, J., Zhang, H.-H., Wu, Y.-G., Gu, T.-J., Yu, X.-H., Jiang, C.-L., Chen, Y., Li, W., & Kong, W.
- Affiliations
- Jilin University (CN)
- Corresponding author
- Chen, Yan
- Kong, Wei
- Venue
- Amino Acids
- Published
- 2012-06-07
- Volume
- 43
- Issue
- 6
- Pages
- 2431-2441
- ISSN
- 0939-4451 (ISSN-L)
- 1438-2199
- OpenAlex
- W2076248750
- Cited by
- 36
- References
- 35
- Citations by year
- 2026: 1 · 2025: 2 · 2023: 5 · 2022: 1 · 2021: 2 · 2020: 5 · 2019: 2 · 2018: 3 · 2017: 1 · 2016: 6 · 2015: 5 · 2014: 3
- FWCI
- 0.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Amino Acids (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Keywords
- N-methylation, reactive oxygen species scavenging, hydrogen peroxide scavenging, intestinal permeability, oral drug delivery, enzymatic stability, proteolysis, Caco-2 cell monolayers, everted gut sac
- MeSH terms
- Animals, Enzyme Stability, Hemin, Humans, Intestinal Mucosa, Methylation, Peroxidase, Oligopeptides, Permeability, Substrate Specificity, Caco-2 Cells, Mice
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- Dong, Q.-G., Zhang, Y., Wang, M.-S., Feng, J., Zhang, H.-H., Wu, Y.-G., Gu, T.-J., Yu, X.-H., Jiang, C.-L., Chen, Y., Li, W., & Kong, W. (2012). Improvement of enzymatic stability and intestinal permeability of deuterohemin-peptide conjugates by specific multi-site N-methylation. Amino Acids. https://doi.org/10.1007/s00726-012-1322-y
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