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

Research output: Contribution to journalArticle

2 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
JournaleLife
Volume7
Early online date31 May 2018
DOIs
Publication statusE-pub ahead of print - 31 May 2018

Fingerprint

Glycosphingolipids
Sorting
Glucagon-Like Peptide 1
Peptides
Ceramides
Incretins
Active Biological Transport
Cell membranes
Therapeutics
Intraperitoneal Injections
Drug delivery
Biological Availability
Stomach
Fatty Acids
Cell Membrane
Hormones
Technology
Lipids
Glucose
Molecules

ASJC Scopus subject areas

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

Cite this

Garcia-Castillo, M. D., Chinnapen, D. J. F., Te Welscher, Y. M., Gonzalez, R. J., Softic, S., Pacheco, M., ... Lencer, W. I. (2018). Mucosal absorption of therapeutic peptides by harnessing the endogenous sorting of glycosphingolipids. eLife, 7, [e34469]. https://doi.org/10.7554/eLife.34469

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.; Ronald Kahn, C.; von Andrian, Ulrich H.; Lau, Jesper; Pentelute, Bradley L.; Lencer, Wayne I.

In: eLife, Vol. 7, e34469, 31.05.2018.

Research output: Contribution to journalArticle

Garcia-Castillo, MD, Chinnapen, DJF, Te Welscher, YM, Gonzalez, RJ, Softic, S, Pacheco, M, Mrsny, RJ, Ronald Kahn, C, von Andrian, UH, Lau, J, Pentelute, BL & Lencer, WI 2018, 'Mucosal absorption of therapeutic peptides by harnessing the endogenous sorting of glycosphingolipids', eLife, vol. 7, e34469. https://doi.org/10.7554/eLife.34469
Garcia-Castillo MD, Chinnapen DJF, Te Welscher YM, Gonzalez RJ, Softic S, Pacheco M et al. Mucosal absorption of therapeutic peptides by harnessing the endogenous sorting of glycosphingolipids. eLife. 2018 May 31;7. e34469. https://doi.org/10.7554/eLife.34469
Garcia-Castillo, Maria Daniela ; Chinnapen, Daniel J.F. ; Te Welscher, Yvonne M. ; Gonzalez, Rodrigo J. ; Softic, Samir ; Pacheco, Michele ; Mrsny, Randall J. ; Ronald Kahn, C. ; von Andrian, Ulrich H. ; Lau, Jesper ; Pentelute, Bradley L. ; Lencer, Wayne I. / Mucosal absorption of therapeutic peptides by harnessing the endogenous sorting of glycosphingolipids. In: eLife. 2018 ; Vol. 7.
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