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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:30

Article

Duclos, Richard I., Jr.¹  Blue, Kiara D.^1,5  Rufo, Michael J.¹  Chen, Xiaoling^1,6  Guo, Jason J.²  Ma, Xiaoyu²  Lencer, Wayne, I^1,3,4  Chinnapen, Daniel J. F.^1,3 

[1] Boston Childrens Hosp, Dept Pediat, Div Gastroenterol & Nutr, Boston, MA 02115 USA

[2] Northeastern Univ, Barnett Inst Chem & Biol Anal, Dept Chem & Chem Biol, Boston, MA 02115 USA

[3] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA

[4] Harvard Digest Dis Ctr, Boston, MA 02115 USA

[5] EVIO Labs, Framingham, MA USA

[6] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA USA

关键词: Short-acyl-chain;    C-6-ceramide;    Transcytosis;    Oral peptide delivery;   

DOI  :  10.1016/j.bmcl.2020.127014

来源: Elsevier

【 摘 要 】

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 C-6-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.

【 授权许可】

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