title: CD22-antagonists with nanomolar potency: the synergistic effect of hydrophobic groups at C-2 and C-9 of sialic acid scaffold.
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 (IC(50) 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.
authors.affiliation: Department of Applied Bio-organic Chemistry, Faculty of Applied Biological Sciences, The United Graduate School of Agricultural Sciences, Gifu University, Gifu 501-1193, Japan. moazhajjaj@yahoo.com
authors.forename: Hajjaj H M
authors.initials: HH
authors.lastname: Abdu-Allah
authors.forename: Kozo
authors.initials: K
authors.lastname: Watanabe
authors.forename: Gladys C
authors.initials: GC
authors.lastname: Completo
authors.forename: Magesh
authors.initials: M
authors.lastname: Sadagopan
authors.forename: Koji
authors.initials: K
authors.lastname: Hayashizaki
authors.forename: Chiaki
authors.initials: C
authors.lastname: Takaku
authors.forename: Taichi
authors.initials: T
authors.lastname: Tamanaka
authors.forename: Hiromu
authors.initials: H
authors.lastname: Takematsu
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kozutsumi
authors.forename: James C
authors.initials: JC
authors.lastname: Paulson
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tsubata
authors.forename: Hiromune
authors.initials: H
authors.lastname: Ando
authors.forename: Hideharu
authors.initials: H
authors.lastname: Ishida
authors.forename: Makoto
authors.initials: M
authors.lastname: Kiso
mesh_terms: D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D018992:Myelin-Associated Glycoprotein / Q000037:antagonists & inhibitors / Q000378:metabolism; D019158:N-Acetylneuraminic Acid / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000737:chemistry* / Q000378:metabolism
chemical_list: D018992:Myelin-Associated Glycoprotein; D051918:Sialic Acid Binding Ig-like Lectin 2; D019158:N-Acetylneuraminic Acid