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

doi:10.7554/eLife.34469

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

Department of Life Sciences

Research output: Contribution to journal › Article › peer-review

16 Citations (SciVal)

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 language	English
Article number	e34469
Pages (from-to)	1-19
Number of pages	19
Journal	eLife
Volume	7
Early online date	31 May 2018
DOIs	https://doi.org/10.7554/eLife.34469
Publication status	Published - 31 May 2018

Bibliographical note

Funding

This project was supported by a NIH F-32 DK111072-01 to MDG-C; DK084424, DK048106, DK104868, and an unrestricted innovator grant from Novo Nordisk to WIL; DK104868 to DC.; DK031036 to C RK.; HD000850 to SS.; T32 DK007477 to RJG; and PO1 AI112521 and RO1 AR068383 to Uv-A. We acknowledge the Harvard Digestive Disease Center DK034854 and the Harvard Medical School Center for Immune Imaging. We are grateful to Dr. Elisha Fielding for helping to develop animal tissue harvesting protocols and Kiara Blue for chemical synthesis of lipid-peptide fusions, as well as members of the Lencer laboratory for their helpful discussions. An innovator grant and collaboration with Novo Nordisk was awarded to WIL with no restrictions for initial studies on peptide reporter design (2012–2014). Novo Nordisk declined any and all claims to the technology in 2015.

ASJC Scopus subject areas

General Neuroscience
General Biochemistry,Genetics and Molecular Biology
General Immunology and Microbiology

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10.7554/eLife.34469Licence: CC BY

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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. Article e34469. https://doi.org/10.7554/eLife.34469

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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.",

author = "Garcia-Castillo, {Maria Daniela} and Chinnapen, {Daniel J.F.} and {Te Welscher}, {Yvonne M.} and Gonzalez, {Rodrigo J.} and Samir Softic and Michele Pacheco and Mrsny, {Randall J.} and {Ronald Kahn}, C. and {von Andrian}, {Ulrich H.} and Jesper Lau and Pentelute, {Bradley L.} and Lencer, {Wayne I.}",

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AU - Chinnapen, Daniel J.F.

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AU - Gonzalez, Rodrigo J.

AU - Softic, Samir

AU - Pacheco, Michele

AU - Mrsny, Randall J.

AU - Ronald Kahn, C.

AU - von Andrian, Ulrich H.

AU - Lau, Jesper

AU - Pentelute, Bradley L.

AU - Lencer, Wayne I.

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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