Mucosal absorption of therapeutic peptides by harnessing the endogenous sorting of glycosphingolipids
Transport of biologically active molecules across tight epithelial barriers is a major challenge preventing therapeutic peptides from oral drug delivery. Here, we identify a set of synthetic glycosphingolipids that harness the endogenous process of intracellular lipid-sorting to enable mucosal absor...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2018-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/34469 |
| _version_ | 1811181433393250304 |
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| author | Maria Daniela Garcia-Castillo Daniel J-F Chinnapen Yvonne M te Welscher Rodrigo J Gonzalez Samir Softic Michele Pacheco Randall J Mrsny C Ronald Kahn Ulrich H von Andrian Jesper Lau Bradley L Pentelute Wayne I Lencer |
| author_facet | Maria Daniela Garcia-Castillo Daniel J-F Chinnapen Yvonne M te Welscher Rodrigo J Gonzalez Samir Softic Michele Pacheco Randall J Mrsny C Ronald Kahn Ulrich H von Andrian Jesper Lau Bradley L Pentelute Wayne I Lencer |
| author_sort | Maria Daniela Garcia-Castillo |
| collection | DOAJ |
| description | Transport of biologically active molecules across tight epithelial barriers is a major challenge preventing therapeutic peptides from oral drug delivery. Here, we identify a set of synthetic glycosphingolipids that harness the endogenous process of intracellular lipid-sorting to enable mucosal absorption of the incretin hormone GLP-1. Peptide cargoes covalently fused to glycosphingolipids with ceramide domains containing C6:0 or smaller fatty acids were transported with 20-100-fold greater efficiency across epithelial barriers in vitro and in vivo. This was explained by structure-function of the ceramide domain in intracellular sorting and by the affinity of the glycosphingolipid species for insertion into and retention in cell membranes. In mice, GLP-1 fused to short-chain glycosphingolipids was rapidly and systemically absorbed after gastric gavage to affect glucose tolerance with serum bioavailability comparable to intraperitoneal injection of GLP-1 alone. This is unprecedented for mucosal absorption of therapeutic peptides, and defines a technology with many other clinical applications. |
| first_indexed | 2024-04-11T09:16:43Z |
| format | Article |
| id | doaj.art-10a0616a7f8144d69071f2819bf380d6 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:16:43Z |
| publishDate | 2018-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-10a0616a7f8144d69071f2819bf380d62022-12-22T04:32:18ZengeLife Sciences Publications LtdeLife2050-084X2018-05-01710.7554/eLife.34469Mucosal absorption of therapeutic peptides by harnessing the endogenous sorting of glycosphingolipidsMaria Daniela Garcia-Castillo0https://orcid.org/0000-0002-8456-2531Daniel J-F Chinnapen1https://orcid.org/0000-0003-3100-3346Yvonne M te Welscher2Rodrigo J Gonzalez3Samir Softic4Michele Pacheco5Randall J Mrsny6C Ronald Kahn7Ulrich H von Andrian8Jesper Lau9Bradley L Pentelute10Wayne I Lencer11https://orcid.org/0000-0001-7346-2730Division of Gastroenterology, Boston Children's Hospital, Boston, United StatesDivision of Gastroenterology, Boston Children's Hospital, Boston, United States; Department of Pediatrics, Harvard Medical School, Boston, United States; Harvard Digestive Diseases Center, Boston, United StatesDivision of Gastroenterology, Boston Children's Hospital, Boston, United StatesDepartment of Microbiology and Immunobiology, Harvard Medical School, Boston, United States; Center for Immune Imaging, Harvard Medical School, Boston, United StatesJoslin Diabetes Center and Harvard Medical School, Boston, United StatesDivision of Gastroenterology, Boston Children's Hospital, Boston, United StatesDepartment of Pharmacy and Pharmacology, Univeristy of Bath, Bath, United KingdomJoslin Diabetes Center and Harvard Medical School, Boston, United StatesDepartment of Microbiology and Immunobiology, Harvard Medical School, Boston, United States; Center for Immune Imaging, Harvard Medical School, Boston, United StatesNovo Nordisk, Måløv, DenmarkDepartment of Chemistry, Massachusetts Institute of Technology, Cambridge, United StatesDivision of Gastroenterology, Boston Children's Hospital, Boston, United States; Harvard Digestive Diseases Center, Boston, United States; Department of Pediatrics, Harvard Medical School, Boston, United StatesTransport of biologically active molecules across tight epithelial barriers is a major challenge preventing therapeutic peptides from oral drug delivery. Here, we identify a set of synthetic glycosphingolipids that harness the endogenous process of intracellular lipid-sorting to enable mucosal absorption of the incretin hormone GLP-1. Peptide cargoes covalently fused to glycosphingolipids with ceramide domains containing C6:0 or smaller fatty acids were transported with 20-100-fold greater efficiency across epithelial barriers in vitro and in vivo. This was explained by structure-function of the ceramide domain in intracellular sorting and by the affinity of the glycosphingolipid species for insertion into and retention in cell membranes. In mice, GLP-1 fused to short-chain glycosphingolipids was rapidly and systemically absorbed after gastric gavage to affect glucose tolerance with serum bioavailability comparable to intraperitoneal injection of GLP-1 alone. This is unprecedented for mucosal absorption of therapeutic peptides, and defines a technology with many other clinical applications.https://elifesciences.org/articles/34469glycolipids/gangliosideslipid sortingdrug deliveryGLP-1/ diabetesmembrane transportepithelial cells |
| spellingShingle | Maria Daniela Garcia-Castillo Daniel J-F Chinnapen Yvonne M te Welscher Rodrigo J Gonzalez Samir Softic Michele Pacheco Randall J Mrsny C Ronald Kahn Ulrich H von Andrian Jesper Lau Bradley L Pentelute Wayne I Lencer Mucosal absorption of therapeutic peptides by harnessing the endogenous sorting of glycosphingolipids eLife glycolipids/gangliosides lipid sorting drug delivery GLP-1/ diabetes membrane transport epithelial cells |
| title | Mucosal absorption of therapeutic peptides by harnessing the endogenous sorting of glycosphingolipids |
| title_full | Mucosal absorption of therapeutic peptides by harnessing the endogenous sorting of glycosphingolipids |
| title_fullStr | Mucosal absorption of therapeutic peptides by harnessing the endogenous sorting of glycosphingolipids |
| title_full_unstemmed | Mucosal absorption of therapeutic peptides by harnessing the endogenous sorting of glycosphingolipids |
| title_short | Mucosal absorption of therapeutic peptides by harnessing the endogenous sorting of glycosphingolipids |
| title_sort | mucosal absorption of therapeutic peptides by harnessing the endogenous sorting of glycosphingolipids |
| topic | glycolipids/gangliosides lipid sorting drug delivery GLP-1/ diabetes membrane transport epithelial cells |
| url | https://elifesciences.org/articles/34469 |
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