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

ELife
Maria Daniela Garcia-CastilloWayne I Lencer

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.

References

Mar 24, 1999·The Journal of Cell Biology·S MukherjeeF R Maxfield
Jun 30, 2000·Current Opinion in Cell Biology·K E MostovY Altschuler
Jul 5, 2003·Physiological Reviews·Pamela L Tuma, Ann L Hubbard
Jan 22, 2004·The Journal of Biological Chemistry·Mingming HaoFrederick R Maxfield
May 14, 2004·Annual Review of Biophysics and Biomolecular Structure·Kai Simons, Winchil L C Vaz
Dec 13, 2006·FEMS Microbiology Letters·Daniel J-F ChinnapenWayne I Lencer
Dec 5, 2008·Bioconjugate Chemistry·Anouk Dirksen, Philip E Dawson
May 18, 2011·Cold Spring Harbor Perspectives in Biology·Helge Ewers, Ari Helenius
Jul 16, 2011·Current Topics in Microbiology and Immunology·Robert A Spooner, J Michael Lord
Sep 29, 2011·Chemistry and Physics of Lipids·Laura CantùAlessandro Prinetti
Aug 25, 2012·Frontiers in Cellular and Infection Microbiology·Jin A ChoRamiro Massol
Apr 24, 2013·Journal of Inherited Metabolic Disease·N Joan Abbott
Dec 11, 2013·The Journal of Endocrinology·L van BloemendaalM Diamant
Dec 29, 2013·Journal of Controlled Release : Official Journal of the Controlled Release Society·Yvonne M te WelscherWayne I Lencer
Oct 14, 2014·Advances in Pharmacology·Jane E PrestonDavid J Begley
Oct 24, 2014·Annual Review of Pharmacology and Toxicology·Jason M Lajoie, Eric V Shusta
Feb 12, 2015·Clinical Pharmacology and Therapeutics·W M Pardridge
Apr 9, 2015·Frontiers in Neuroscience·Kristy M Heppner, Diego Perez-Tilve
Jan 11, 2017·The Journal of Cell Biology·Bradlee NelmsWayne Lencer
Feb 19, 2017·Cold Spring Harbor Perspectives in Biology·Maria Daniela Garcia-CastilloWayne I Lencer
Apr 27, 2017·Annals of Pediatric Endocrinology & Metabolism·Seungah Lee, Dong Yun Lee
Dec 7, 2018·Bio-protocol·Maria Daniela Garcia-CastilloDaniel J-F Chinnapen

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Citations

Dec 14, 2019·Advanced Materials·Shiran FerberNatalie Artzi
Dec 7, 2018·Bio-protocol·Maria Daniela Garcia-CastilloDaniel J-F Chinnapen
Dec 14, 2018·Cellular and Molecular Life Sciences : CMLS·Roberto VillaseñorLudovic Collin
Jun 2, 2020·Advanced Drug Delivery Reviews·D J BraydenR J Mrsny
Jun 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ludger Johannes
Jun 18, 2021·Nature Communications·Senthil ArumugamLudger Johannes
Feb 16, 2019·Journal of the American Chemical Society·Alexander A VinogradovHiroaki Suga
Aug 27, 2021·Toxins·Anne K KenworthyWayne I Lencer

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Methods Mentioned

BETA
confocal microscopy
affinity purification
transfection
PCR

Software Mentioned

GraphPad PRISM

Related Concepts

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