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: | , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications, Ltd.
2020
|
| Subjects: | |
| Online Access: | https://hdl.handle.net/1721.1/123515 |
| _version_ | 1811081325889716224 |
|---|---|
| author | Garcia-Castillo, Maria Daniela Chinnapen, Daniel J F te Welscher, Yvonne M Gonzalez, Rodrigo J Softic, Samir Pacheco, Michele Mrsny, Randall J Kahn, C Ronald von Andrian, Ulrich H Lau, Jesper Pentelute, Bradley L. Lencer, Wayne I |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Garcia-Castillo, Maria Daniela Chinnapen, Daniel J F te Welscher, Yvonne M Gonzalez, Rodrigo J Softic, Samir Pacheco, Michele Mrsny, Randall J Kahn, C Ronald von Andrian, Ulrich H Lau, Jesper Pentelute, Bradley L. Lencer, Wayne I |
| author_sort | Garcia-Castillo, Maria Daniela |
| collection | MIT |
| 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 | 2024-09-23T11:45:01Z |
| format | Article |
| id | mit-1721.1/123515 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T11:45:01Z |
| publishDate | 2020 |
| publisher | eLife Sciences Publications, Ltd. |
| record_format | dspace |
| spelling | mit-1721.1/1235152022-09-27T21:40:07Z Mucosal absorption of therapeutic peptides by harnessing the endogenous sorting of glycosphingolipids Garcia-Castillo, Maria Daniela Chinnapen, Daniel J F te Welscher, Yvonne M Gonzalez, Rodrigo J Softic, Samir Pacheco, Michele Mrsny, Randall J Kahn, C Ronald von Andrian, Ulrich H Lau, Jesper Pentelute, Bradley L. Lencer, Wayne I Massachusetts Institute of Technology. Department of Chemistry General Biochemistry, Genetics and Molecular Biology General Immunology and Microbiology General Neuroscience General Medicine 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. 2020-01-21T21:39:34Z 2020-01-21T21:39:34Z 2018-11-09 2018-05-31 2020-01-02T18:47:02Z Article http://purl.org/eprint/type/JournalArticle 2050-084X https://hdl.handle.net/1721.1/123515 Garcia-Castillo, Maria Daniela et al. "Mucosal absorption of therapeutic peptides by harnessing the endogenous sorting of glycosphingolipids." eLife, 7, (November 2018): e34469 © The Authors en 10.7554/elife.34469 eLIfe Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf eLife Sciences Publications, Ltd. eLife |
| spellingShingle | General Biochemistry, Genetics and Molecular Biology General Immunology and Microbiology General Neuroscience General Medicine Garcia-Castillo, Maria Daniela Chinnapen, Daniel J F te Welscher, Yvonne M Gonzalez, Rodrigo J Softic, Samir Pacheco, Michele Mrsny, Randall J Kahn, C Ronald von Andrian, Ulrich H Lau, Jesper Pentelute, Bradley L. Lencer, Wayne I Mucosal absorption of therapeutic peptides by harnessing the endogenous sorting of glycosphingolipids |
| 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 | General Biochemistry, Genetics and Molecular Biology General Immunology and Microbiology General Neuroscience General Medicine |
| url | https://hdl.handle.net/1721.1/123515 |
| work_keys_str_mv | AT garciacastillomariadaniela mucosalabsorptionoftherapeuticpeptidesbyharnessingtheendogenoussortingofglycosphingolipids AT chinnapendanieljf mucosalabsorptionoftherapeuticpeptidesbyharnessingtheendogenoussortingofglycosphingolipids AT tewelscheryvonnem mucosalabsorptionoftherapeuticpeptidesbyharnessingtheendogenoussortingofglycosphingolipids AT gonzalezrodrigoj mucosalabsorptionoftherapeuticpeptidesbyharnessingtheendogenoussortingofglycosphingolipids AT softicsamir mucosalabsorptionoftherapeuticpeptidesbyharnessingtheendogenoussortingofglycosphingolipids AT pachecomichele mucosalabsorptionoftherapeuticpeptidesbyharnessingtheendogenoussortingofglycosphingolipids AT mrsnyrandallj mucosalabsorptionoftherapeuticpeptidesbyharnessingtheendogenoussortingofglycosphingolipids AT kahncronald mucosalabsorptionoftherapeuticpeptidesbyharnessingtheendogenoussortingofglycosphingolipids AT vonandrianulrichh mucosalabsorptionoftherapeuticpeptidesbyharnessingtheendogenoussortingofglycosphingolipids AT laujesper mucosalabsorptionoftherapeuticpeptidesbyharnessingtheendogenoussortingofglycosphingolipids AT pentelutebradleyl mucosalabsorptionoftherapeuticpeptidesbyharnessingtheendogenoussortingofglycosphingolipids AT lencerwaynei mucosalabsorptionoftherapeuticpeptidesbyharnessingtheendogenoussortingofglycosphingolipids |