Identification of a Self-Assembling Small-Molecule Cancer Vaccine Adjuvant with an Improved Toxicity Profile

  • J Med Chem. 2023 Sep 28;66(18):13266-13279. doi: 10.1021/acs.jmedchem.3c01252.
Shao-Hua Zhuo  1 ,  Naotaka Noda  2  3 ,  Kou Hioki  4 ,  Shuyu Jin  2  3 ,  Tomoya Hayashi  4 ,  Kou Hiraga  5 ,  Haruka Momose  5 ,  Wen-Hao Li  1 ,  Lang Zhao  1 ,  Takuo Mizukami  5 ,  Ken J Ishii  4 ,  Yan-Mei Li  1  6  7 ,  Motonari Uesugi  3  8  9
Affiliations
  • 1. Key Lab of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084, China.
  • 2. Graduate School of Medicine, Kyoto University, Uji 611-0011, Kyoto, Japan.
  • 3. Institute for Chemical Research, Kyoto University, Uji 611-0011, Kyoto, Japan.
  • 4. Division of Vaccine Science, The Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
  • 5. Research Center for Biological Products in the Next Generation, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.
  • 6. Beijing Institute for Brain Disorders, Beijing 100069, China.
  • 7. Center for Synthetic and Systems Biology, Tsinghua University, Beijing 100084, China.
  • 8. Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8501, Japan.
  • 9. School of Pharmacy, Fudan University, Shanghai 201203, China.
PMID: 37676021 DOI: 10.1021/acs.jmedchem.3c01252
Abstract

Protein or peptide Cancer vaccines usually include immune potentiators, so-called adjuvants. However, it remains challenging to identify structurally simple, chemically accessible synthetic molecules that are effective and safe as vaccine Adjuvant. Here, we present cholicamideβ (6), a self-assembling small-molecule vaccine Adjuvant with an improved toxicity profile and proven efficacy in vivo. We demonstrate that cholicamideβ (6), which is less cytotoxic than its parent compound, forms virus-like particles to potently activate dendritic cells with the concomitant secretion of cytokines. When combined with a peptide antigen, cholicamideβ (6) potentiated the antigen presentation on dendritic cells to induce antigen-specific T cells. As a therapeutic Cancer vaccine Adjuvant in mice, a mixture of cholicamideβ (6) and a peptide antigen protected mice from the challenges of malignant Cancer cells without overt toxicity. Cholicamideβ (6) may offer a translational opportunity as an unprecedented class of small-molecule Cancer vaccine adjuvants.

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