Synthesis and immunological evaluation of the unnatural β-linked mucin-1 Thomsen-Friedenreich conjugate

Org Biomol Chem. 2021 Mar 21;19(11):2448-2455. doi: 10.1039/d1ob00007a. Epub 2021 Mar 1.


MUC1 glycopeptides are attractive antigens for anti-cancer vaccine development. One potential drawback in using the native MUC1 glycopeptide for vaccine design is the instability of the O-glycosyl linkage between the glycan and the peptide backbone to glycosidase. To overcome this challenge, a MUC1 glycopeptide mimic has been synthesized with the galactose-galactosamine disaccharide linked with threonine (Thomsen-Friedenreich or Tf antigen) through an unnatural β-glycosyl bond. The resulting MUC1-β-Tf had a much-enhanced stability toward a glycosidase capable of cleaving the glycan from the corresponding MUC1 glycopeptide with the natural α-Tf linkage. The MUC1-β-Tf was subsequently conjugated with a powerful carrier bacteriophage Qβ. The conjugate induced high levels of IgG antibodies in clinically relevant human MUC1 transgenic mice, which cross-recognized not only the natural MUC1-α-Tf glycopeptide but also MUC1 expressing tumor cells, supporting the notion that a simple switch of the stereochemistry of the glycan/peptide linkage can be a strategy for anti-cancer vaccine epitope design for glycopeptides.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Tumor-Associated, Carbohydrate / chemistry*
  • Cancer Vaccines / chemistry*
  • Cancer Vaccines / immunology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Disaccharides / chemistry
  • Drug Design
  • Galactosamine / chemistry
  • Galactose / chemistry
  • Glycopeptides / chemistry*
  • Humans
  • Immunoglobulin G / chemistry
  • Immunoglobulin G / pharmacology
  • Mice
  • Mice, Transgenic
  • Mucin-1 / chemistry*
  • Mucin-1 / immunology


  • Antigens, Tumor-Associated, Carbohydrate
  • Cancer Vaccines
  • Disaccharides
  • Glycopeptides
  • Immunoglobulin G
  • MUC1 protein, human
  • Mucin-1
  • Thomsen-Friedenreich antigen
  • Galactosamine
  • Galactose