Mucosal absorption of therapeutic peptides by harnessing the endogenous sorting of glycosphingolipids
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; Pentelute, Bradley L.; Lencer, Wayne I; ... Show more Show less
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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.
DepartmentMassachusetts Institute of Technology. Department of Chemistry
eLife Sciences Publications, Ltd.
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
Final published version
General Biochemistry, Genetics and Molecular Biology, General Immunology and Microbiology, General Neuroscience, General Medicine