Taherali, F;
Chouhan, N;
Wang, F;
Lavielle, S;
Baran, M;
McCoubrey, LE;
Basit, AW;
(2023)
Impact of Peptide Structure on Colonic Stability and Tissue Permeability.
Pharmaceutics
, 15
(7)
, Article 1956. 10.3390/pharmaceutics15071956.
Preview |
PDF
pharmaceutics-15-01956.pdf - Published Version Download (6MB) | Preview |
Abstract
Most marketed peptide drugs are administered parenterally due to their inherent gastrointestinal (GI) instability and poor permeability across the GI epithelium. Several molecular design techniques, such as cyclisation and D-amino acid (D-AA) substitution, have been proposed to improve oral peptide drug bioavailability. However, very few of these techniques have been translated to the clinic. In addition, little is known about how synthetic peptide design may improve stability and permeability in the colon, a key site for the treatment of inflammatory bowel disease and colorectal cancer. In this study, we investigated the impact of various cyclisation modifications and D-AA substitutions on the enzymatic stability and colonic tissue permeability of native oxytocin and 11 oxytocin-based peptides. Results showed that the disulfide bond cyclisation present in native oxytocin provided an improved stability in a human colon model compared to a linear oxytocin derivative. Chloroacetyl cyclisation increased native oxytocin stability in the colonic model at 1.5 h by 30.0%, whereas thioether and N-terminal acetylated cyclisations offered no additional protection at 1.5 h. The site and number of D-AA substitutions were found to be critical for stability, with three D-AAs at Tyr, Ile and Leu, improving native oxytocin stability at 1.5 h in both linear and cyclic structures by 58.2% and 79.1%, respectively. Substitution of three D-AAs into native cyclic oxytocin significantly increased peptide permeability across rat colonic tissue; this may be because D-AA substitution favourably altered the peptide’s secondary structure. This study is the first to show how the strategic design of peptide therapeutics could enable their delivery to the colon via the oral route.
| Type: | Article |
|---|---|
| Title: | Impact of Peptide Structure on Colonic Stability and Tissue Permeability |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3390/pharmaceutics15071956 |
| Publisher version: | https://doi.org/10.3390/pharmaceutics15071956 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | Oral delivery of biologics and peptides; colonic drug delivery; peptide design and synthesis; gastrointestinal peptide stability; microbiota drug metabolism; bioavailability of biopharmaceuticals |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Mechanical Engineering |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10174968 |
Archive Staff Only
 |
View Item |
