Division of Gastroenterology and Nutrition, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, United States.
Barnett Institute for Chemical and Biological Analysis, Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, United States.
Bioorg Med Chem Lett. 2020 Apr 15;30(8):127014. doi: 10.1016/j.bmcl.2020.127014. Epub 2020 Feb 7.
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-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.
有效的治疗性肽和其他药物分子穿过紧密的上皮屏障的转运将克服口服给药的主要障碍。我们已经证明，与神经节苷脂（GM1 和 GM3）连接的肽具有非天然的短酰基，劫持内源性的细胞内脂质分选过程，导致转胞吞作用和在体外和体内穿过上皮屏障的传递。在这里，我们报告了将肽直接共价连接到短酰基链 C-神经酰胺的合成方法。我们发现短酰基链神经酰胺结构域是体外转胞吞作用的唯一原因。这阐明并扩展了短酰基神经鞘脂用于共轭肽穿过紧密的黏膜细胞屏障的传递平台，从神经节苷脂到神经酰胺本身。
