Abstract:
: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.
journal_name
Elifejournal_title
eLifeauthors
Garcia-Castillo MD,Chinnapen DJ,Te Welscher YM,Gonzalez RJ,Softic S,Pacheco M,Mrsny RJ,Kahn CR,von Andrian UH,Lau J,Pentelute BL,Lencer WIdoi
10.7554/eLife.34469subject
Has Abstractpub_date
2018-05-31 00:00:00issn
2050-084Xpii
34469journal_volume
7pub_type
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