{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:45:24Z","timestamp":1790394324766,"version":"4.1.0"},"reference-count":75,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,7,15]],"date-time":"2023-07-15T00:00:00Z","timestamp":1689379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000266","name":"Intract Pharma Ltd., Orbit Discovery, Engineering and Physical Sciences Research Council","doi-asserted-by":"publisher","award":["EP\/S023054\/1"],"award-info":[{"award-number":["EP\/S023054\/1"]}],"id":[{"id":"10.13039\/501100000266","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>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\u2019s 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.<\/jats:p>","DOI":"10.3390\/pharmaceutics15071956","type":"journal-article","created":{"date-parts":[[2023,7,17]],"date-time":"2023-07-17T00:41:05Z","timestamp":1689554465000},"page":"1956","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Impact of Peptide Structure on Colonic Stability and Tissue Permeability"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-5882-4368","authenticated-orcid":false,"given":"Farhan","family":"Taherali","sequence":"first","affiliation":[{"name":"Intract Pharma Ltd., London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK"},{"name":"Sygnature Discovery, Bio City, Pennyfoot Street, Nottingham NG1 1GR, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nerisha","family":"Chouhan","sequence":"additional","affiliation":[{"name":"Intract Pharma Ltd., London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanjin","family":"Wang","sequence":"additional","affiliation":[{"name":"Intract Pharma Ltd., London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastien","family":"Lavielle","sequence":"additional","affiliation":[{"name":"Orbit Discovery, Schrodinger Building, Heatley Rd, Oxford OX4 4GE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3176-2425","authenticated-orcid":false,"given":"Maryana","family":"Baran","sequence":"additional","affiliation":[{"name":"Orbit Discovery, Schrodinger Building, Heatley Rd, Oxford OX4 4GE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura E.","family":"McCoubrey","sequence":"additional","affiliation":[{"name":"UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5368-6603","authenticated-orcid":false,"given":"Abdul W.","family":"Basit","sequence":"additional","affiliation":[{"name":"UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vipul","family":"Yadav","sequence":"additional","affiliation":[{"name":"Intract Pharma Ltd., London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1038\/s41392-022-00904-4","article-title":"Therapeutic peptides: Current applications and future directions","volume":"7","author":"Wang","year":"2022","journal-title":"Signal Transduct. 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