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

• Main Authors: Garcia-Castillo, Maria Daniela (Author), Chinnapen, Daniel J F (Author), te Welscher, Yvonne M (Author), Gonzalez, Rodrigo J (Author), Softic, Samir (Author), Pacheco, Michele (Author), Mrsny, Randall J (Author), Kahn, C Ronald (Author), von Andrian, Ulrich H (Author), Lau, Jesper (Author), Pentelute, Bradley L. (Author), Lencer, Wayne I (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Chemistry (Contributor)
• Format: Article
• Language: English
• Published: eLife Sciences Publications, Ltd., 2020-01-21T21:39:34Z.
• Subjects: Article
• Online Access: Get fulltext

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.