CD22-Antagonists with nanomolar potency: The synergistic effect of hydrophobic groups at C-2 and C-9 of sialic acid scaffold

Hajjaj H.M. Abdu-Allah, Kozo Watanabe, Gladys C. Completo, Magesh Sadagopan, Koji Hayashizaki, Chiaki Takaku, Taichi Tamanaka, Hiromu Takematsu, Yasunori Kozutsumi, James C. Paulson, Takeshi Tsubata, Hiromune Ando, Hideharu Ishida, Makoto Kiso

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

Abstract

In earlier studies, we identified the C-9 amido derivative 1 (9-(4′-hydroxy-4-biphenyl)acetamido-9-deoxy-Neu5Gcα2-6GalOMP) and the C-9 amino derivative 2 (9-(4′-hydroxy-4-biphenyl)methylamino-9-deoxy- Neu5Gcα2-6GalOMP) have the most promising affinity for mouse CD22 and human CD22, respectively. Replacing the subterminal galactose residue (2-6Gal-OMP) of 1 with benzyl (5) or biphenylmethyl (6) as aglycone led to even higher potency for mCD22. In this study, both compounds showed improved potency and selectivity for CD22 (IC50 70 nM) and 712-fold more selective for CD22 than for MAG. The corresponding derivatives of 2, compounds 8 and 9, showed comparable activity to 2 but lower potency and selectivity than 5 and 6. Although compounds 5-9 are simple and small molecular weight antagonists, they showed much high potency and selectivity than the corresponding compounds having α 2-6Gal linkage. Both biological and computational docking simulation studies suggest that the 2-6Gal-OMP residues of 1 and 2 are not critical for binding process and could be replaced with hydrophobic non-carbohydrate moieties. The data presented herein has significant implications for the design and discovery of next-generation CD22-antagonists.

Original languageEnglish
Pages (from-to)1966-1971
Number of pages6
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number6
DOIs
Publication statusPublished - 15-03-2011
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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