Impact of Peptide Structure on Colonic Stability and Tissue Permeability
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...
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| Format: | Article |
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MDPI AG
2023-07-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/7/1956 |
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| author | Farhan Taherali Nerisha Chouhan Fanjin Wang Sebastien Lavielle Maryana Baran Laura E. McCoubrey Abdul W. Basit Vipul Yadav |
| author_facet | Farhan Taherali Nerisha Chouhan Fanjin Wang Sebastien Lavielle Maryana Baran Laura E. McCoubrey Abdul W. Basit Vipul Yadav |
| author_sort | Farhan Taherali |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T00:44:13Z |
| format | Article |
| id | doaj.art-ba233770da3d491cb250517e1d06cea2 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-11T00:44:13Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-ba233770da3d491cb250517e1d06cea22023-11-18T20:56:12ZengMDPI AGPharmaceutics1999-49232023-07-01157195610.3390/pharmaceutics15071956Impact of Peptide Structure on Colonic Stability and Tissue PermeabilityFarhan Taherali0Nerisha Chouhan1Fanjin Wang2Sebastien Lavielle3Maryana Baran4Laura E. McCoubrey5Abdul W. Basit6Vipul Yadav7Intract Pharma Ltd., London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UKIntract Pharma Ltd., London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UKIntract Pharma Ltd., London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UKOrbit Discovery, Schrodinger Building, Heatley Rd, Oxford OX4 4GE, UKOrbit Discovery, Schrodinger Building, Heatley Rd, Oxford OX4 4GE, UKUCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UKUCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UKIntract Pharma Ltd., London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UKMost 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.https://www.mdpi.com/1999-4923/15/7/1956oral delivery of biologics and peptidescolonic drug deliverypeptide design and synthesisgastrointestinal peptide stabilitymicrobiota drug metabolismbioavailability of biopharmaceuticals |
| spellingShingle | Farhan Taherali Nerisha Chouhan Fanjin Wang Sebastien Lavielle Maryana Baran Laura E. McCoubrey Abdul W. Basit Vipul Yadav Impact of Peptide Structure on Colonic Stability and Tissue Permeability Pharmaceutics oral delivery of biologics and peptides colonic drug delivery peptide design and synthesis gastrointestinal peptide stability microbiota drug metabolism bioavailability of biopharmaceuticals |
| title | Impact of Peptide Structure on Colonic Stability and Tissue Permeability |
| title_full | Impact of Peptide Structure on Colonic Stability and Tissue Permeability |
| title_fullStr | Impact of Peptide Structure on Colonic Stability and Tissue Permeability |
| title_full_unstemmed | Impact of Peptide Structure on Colonic Stability and Tissue Permeability |
| title_short | Impact of Peptide Structure on Colonic Stability and Tissue Permeability |
| title_sort | impact of peptide structure on colonic stability and tissue permeability |
| topic | oral delivery of biologics and peptides colonic drug delivery peptide design and synthesis gastrointestinal peptide stability microbiota drug metabolism bioavailability of biopharmaceuticals |
| url | https://www.mdpi.com/1999-4923/15/7/1956 |
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