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Improved synthesis of CD22-binding sialosides and its application for further development of potent CD22 inhibitors

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Abstract

CD22, one of the sialic acid-binding immunoglobulin-like lectins (Siglecs), regulates B lymphocyte signaling via its interaction with glycan ligands bearing the sequence Neu5Ac/Gcα(2→6)Gal. We have developed the synthetic sialoside GSC-718 as a ligand mimic for CD22 and identified it as a potent CD22 inhibitor. Although the synthesis of CD22-binding sialosides including GSC-718 has been reported by our group, the synthetic route was unfortunately not suitable for large-scale synthesis. In this study, we developed an improved scalable synthetic procedure for sialosides which utilized 1,5-lactam formation as a key step. The improved procedure yielded sialosides incorporating a series of aglycones at the C2 position. Several derivatives with substituted benzyl residues as aglycones were found to bind to mouse CD22 with affinity comparable to that of GSC-718. The new procedure developed in this study affords sialosides in sufficient quantities for cell-based assays, and will facilitate the search for promising CD22 inhibitors that have therapeutic potential.

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Funding

This work was funded by Health Labor Sciences Research Grant and the Project from Japan Agency of Medical Research and Development (AMED) JP15ak0101012 (T.T., N.I. and H.I.), JPSP Grant-in-Aid for Scientific Research 23390063 and 26293062 (T.T.), the Joint Usage/Research Program of Medical Research Institute, Tokyo Medical and Dental University (T.T., H.I. and H.T.).

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Authors and Affiliations

  1. Department of Applied Bioorganic Chemistry, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan

    Yuki Suganuma, Akihiro Imamura, Makoto Kiso & Hideharu Ishida

  2. Institute for Glyco-core Research (iGCORE), Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan

    Akihiro Imamura, Hiromune Ando & Hideharu Ishida

  3. Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, 113-8510, Tokyo, Japan

    Takeshi Tsubata

  4. Faculty of Medical Technology, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan

    Hiromu Takematsu

Authors
  1. Yuki Suganuma
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  2. Akihiro Imamura
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  3. Hiromune Ando
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  4. Makoto Kiso
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  5. Hiromu Takematsu
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  6. Takeshi Tsubata
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  7. Hideharu Ishida
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Contributions

YS, AI, and TT performed experiments and analyzed data. HA, HI, and MK designed sialosides. HT prepared and provided materials. HI, MK, and TT designed the study. AI, HI, and TT wrote the manuscript.

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Correspondence to Akihiro Imamura or Hideharu Ishida.

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Suganuma, Y., Imamura, A., Ando, H. et al. Improved synthesis of CD22-binding sialosides and its application for further development of potent CD22 inhibitors. Glycoconj J 40, 225–246 (2023). https://doi.org/10.1007/s10719-023-10098-8

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  • DOI: https://doi.org/10.1007/s10719-023-10098-8

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