Mucosal absorption of therapeutic peptides by harnessing the endogenous sorting of glycosphingolipids
Name
elife-34469-v2.pdf
Description
Published version
Size
2.86 MB
Format
Adobe PDF
Checksum (MD5)
b0c3d34d8ec1f42aed4fd2892a36cb0d
Author(s)
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
Date Issued
November 9, 2018
Journal
eLIfe
Publisher
eLife Sciences Publications, Ltd.
Citation
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
Version
Final published version
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.
Subjects
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology
General Neuroscience
General Medicine
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Terms of Use
Creative Commons Attribution 4.0 International license
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.7554/elife.34469
