(eLife Sciences Publications, Ltd, 2018) Garcia-Castillo, Maria Daniela; Chinnapen, Daniel J-F; te Welscher, Yvonne M; Gonzalez, Rodrigo; Softic, Samir; Pacheco, Michele; Mrsny, Randall J; Kahn, C Ronald; von Andrian-Werburg, Ulrich; Lau, Jesper; Pentelute, Bradley L; Lencer, Wayne
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.
