Mucosal absorption of therapeutic peptides by harnessing the endogenous sorting of glycosphingolipids

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

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5 Citations (Scopus)

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.

Original languageEnglish
Article numbere34469
Pages (from-to)1-19
Number of pages19
JournaleLife
Volume7
Early online date31 May 2018
DOIs
Publication statusPublished - 31 May 2018

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Garcia-Castillo, M. D., Chinnapen, D. J. F., Te Welscher, Y. M., Gonzalez, R. J., Softic, S., Pacheco, M., Mrsny, R. J., Ronald Kahn, C., von Andrian, U. H., Lau, J., Pentelute, B. L., & Lencer, W. I. (2018). Mucosal absorption of therapeutic peptides by harnessing the endogenous sorting of glycosphingolipids. eLife, 7, 1-19. [e34469]. https://doi.org/10.7554/eLife.34469