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Conjugation of peptides to short-acyl-chain ceramides for delivery across mucosal cell barriers.

ABSTRACT: Robust transport of therapeutic peptides and other medicinal molecules across tight epithelial barriers would overcome the major obstacle to oral delivery. We have already demonstrated that peptides conjugated to gangliosides (GM1 and GM3) having non-native short N-acyl groups hijack the endogenous process of intracellular lipid sorting resulting in transcytosis and delivery across epithelial barriers in vitro and in vivo. Here, we report synthetic methodologies to covalently conjugate peptides directly to short-acyl-chain C₆-ceramides. We found that the short-acyl-chain ceramide domain is solely responsible for transcytosis in vitro. This clarifies and expands the platform of short-acyl-chain sphingolipids for conjugated peptide delivery across tight mucosal cell barriers from gangliosides to just the ceramide itself.

SUBMITTER: Duclos RI

PROVIDER: S-EPMC7174066 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Conjugation of peptides to short-acyl-chain ceramides for delivery across mucosal cell barriers.

Duclos Richard I RI Blue Kiara D KD Rufo Michael J MJ Chen Xiaoling X Guo Jason J JJ Ma Xiaoyu X Lencer Wayne I WI Chinnapen Daniel J F DJF

Bioorganic & medicinal chemistry letters 20200207 8

Robust transport of therapeutic peptides and other medicinal molecules across tight epithelial barriers would overcome the major obstacle to oral delivery. We have already demonstrated that peptides conjugated to gangliosides (GM1 and GM3) having non-native short N-acyl groups hijack the endogenous process of intracellular lipid sorting resulting in transcytosis and delivery across epithelial barriers in vitro and in vivo. Here, we report synthetic methodologies to covalently conjugate peptides ...[more]

PMID: 32081448

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