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|a Garcia-Castillo, Maria Daniela
|e author
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|a Massachusetts Institute of Technology. Department of Chemistry
|e contributor
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|a Chinnapen, Daniel J F
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|a te Welscher, Yvonne M
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|a Gonzalez, Rodrigo J
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|a Softic, Samir
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|a Pacheco, Michele
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|a Mrsny, Randall J
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|a Kahn, C Ronald
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|a von Andrian, Ulrich H
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|a Lau, Jesper
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|a Pentelute, Bradley L.
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|a Lencer, Wayne I
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|a Mucosal absorption of therapeutic peptides by harnessing the endogenous sorting of glycosphingolipids
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|b eLife Sciences Publications, Ltd.,
|c 2020-01-21T21:39:34Z.
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|z Get fulltext
|u https://hdl.handle.net/1721.1/123515
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|a 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.
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|a en
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|a General Biochemistry, Genetics and Molecular Biology
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|a General Immunology and Microbiology
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|a General Neuroscience
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|a General Medicine
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|a Article
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|t 10.7554/elife.34469
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|t eLIfe
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