Design, Synthesis, and Immunological Evaluation of a Multicomponent Construct Based on a Glycotripeptoid Core Comprising B and T Cell Epitopes and a Toll-like Receptor 7 Agonist That Elicits Potent Immune Responses

J Med Chem. 2018 Nov 8;61(21):9568-9582. doi: 10.1021/acs.jmedchem.8b00960. Epub 2018 Oct 23.

Abstract

We present here for the first time the synthesis and immunological evaluation of a fully synthetic three-component anticancer vaccine candidate that consists of a β-glycotripeptoid core mimicking a cluster of Tn at the surface of tumor cells (B epitope), conjugated to the OVA 323-339 peptide (T-cell epitope) and a Toll-like receptor 7 (TLR7) agonist for potent adjuvanticity. The immunological evaluation of this construct and of precursor components demonstrated the synergistic activity of the components within the conjugate to stimulate innate and adaptive immune cells (DCs, T-helper, and B-cells). Surprisingly, immunization of mice with the tricomponent GalNAc-based construct elicited a low level of anti-Tn IgG but elicited a very high level of antibodies that recognize the TLR7 agonist. This finding could represent a potential vaccine therapeutic approach for the treatment of some autoimmune diseases such as lupus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Chemistry Techniques, Synthetic
  • Drug Design*
  • Epitopes, B-Lymphocyte / chemistry*
  • Epitopes, T-Lymphocyte / chemistry*
  • Mice
  • Mice, Inbred C57BL
  • Peptidomimetics / chemical synthesis*
  • Peptidomimetics / chemistry
  • Peptidomimetics / immunology
  • Peptidomimetics / pharmacology*
  • Toll-Like Receptor 7 / agonists*

Substances

  • Epitopes, B-Lymphocyte
  • Epitopes, T-Lymphocyte
  • Peptidomimetics
  • Toll-Like Receptor 7