α-1,4-Galactosyltransferase-catalyzed glycosylation of sugar and lipid modified Leu-enkephalins

• Sugar and lipid modified enkephalin peptides were chemically synthesized.
• LgtC galactosyltransferase catalyzed conversion of enkephalin derivatives.
• Galactosylated products were purified in 13–71% yields.
• 5% DMSO increased solubility and enzymatic conversion of lipidated enkephalins.
• LgtC displayed unexpectedly high substrate specificity toward galactosyl moieties.

Glycosylation of therapeutic peptides has been reported to improve delivery and targeting of various vaccines and drugs to specific cells/tissues. However, chemical synthesis of complex oligosaccharide derivatives via conventional methods can be challenging due to the need for several orthogonal hydroxyl group protections. Liposaccharyl galactosyltransferase C, a naturally occurring glycosyltransferase enzyme from Neisseria meningitidis, was found to have the ability to transfer a galactosyl moiety to glyco(lipo)peptides. An enzymatic glycosylation of Leu-enkephalin glyco(lipo)peptides was developed and optimized in this study in order to prepare pain regulating peptides with potentially improved central nervous system delivery.

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