2. Academic Validation
  3. Synthesis and immunostimulatory activity of sugar-conjugated TLR7 ligands

Synthesis and immunostimulatory activity of sugar-conjugated TLR7 ligands

  • Bioorg Med Chem Lett. 2020 Feb 1;30(3):126840. doi: 10.1016/j.bmcl.2019.126840.
Akihito Baba 1,  Masahiro Wakao 2,  Hiroyuki Shinchi 1,  Michael Chan 3,  Tomoko Hayashi 3,  Shiyin Yao 3,  Howard B Cottam 3,  Dennis A Carson 3,  Yasuo Suda 4
Affiliations

Affiliations

  • 1 Department of Chemistry, Biotechnology, and Chemical Engineering, Graduate School of Science and Engineering, Kagoshima University, 1-21-40 Korimoto, Kagoshima 890-0065, Japan.
  • 2 Department of Chemistry, Biotechnology, and Chemical Engineering, Graduate School of Science and Engineering, Kagoshima University, 1-21-40 Korimoto, Kagoshima 890-0065, Japan. Electronic address: wakao@eng.kagoshima-u.ac.jp.
  • 3 Moores Cancer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0695, USA.
  • 4 Department of Chemistry, Biotechnology, and Chemical Engineering, Graduate School of Science and Engineering, Kagoshima University, 1-21-40 Korimoto, Kagoshima 890-0065, Japan; SUDx-Biotec Corporation, 1-41-1 Shiroyama, Kagoshima 890-0013, Japan. Electronic address: ysuda@eng.kagoshima-u.ac.jp.
PMID: 31864800 DOI: 10.1016/j.bmcl.2019.126840
Abstract

Toll-like receptors (TLRs) are a type of Pattern Recognition Receptors (PRRs), which are activated by recognizing pathogen-associated molecular patterns (PAMPs). The activation of TLRs initiates innate immune responses and subsequently leads to adaptive immune responses. TLR agonists are effective immuomodulators in vaccine adjuvants for infectious diseases and Cancer Immunotherapy. In exploring hydrophilic small molecules of TLR7 ligands using the cell-targeted property of a vaccine Adjuvant, we conjugated 1V209, a small TLR7 ligand molecule, with various low or middle molecular weight sugar molecules that work as carriers. The sugar-conjugated 1V209 derivatives showed increased water solubility and higher immunostimulatory activity in both mouse and human cells compared to unmodified 1V209. The improved immunostimulatory potency of sugar-conjugates was attenuated by an inhibitor of endocytic process, cytochalasin D, suggesting that conjugation of sugar moieties may enhance the uptake of TLR7 ligand into the endosomal compartment. Collectively our results support that sugar-conjugated TLR7 ligands are applicable to novel drugs for Cancer and vaccine therapy.

Keywords

Agonist; Ligand; Sugar conjugate; TLR7.

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