TY - JOUR
T1 - Mucosal absorption of therapeutic peptides by harnessing the endogenous sorting of glycosphingolipids
AU - Garcia-Castillo, Maria Daniela
AU - Chinnapen, Daniel J.F.
AU - Te Welscher, Yvonne M.
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.
N1 - © 2018, Garcia-Castillo et al.
PY - 2018/5/31
Y1 - 2018/5/31
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85051993974&partnerID=8YFLogxK
U2 - 10.7554/eLife.34469
DO - 10.7554/eLife.34469
M3 - Article
C2 - 29851380
AN - SCOPUS:85051993974
SN - 2050-084X
VL - 7
SP - 1
EP - 19
JO - eLife
JF - eLife
M1 - e34469
ER -