TY - JOUR
T1 - CD22-Antagonists with nanomolar potency
T2 - The synergistic effect of hydrophobic groups at C-2 and C-9 of sialic acid scaffold
AU - Abdu-Allah, Hajjaj H.M.
AU - Watanabe, Kozo
AU - Completo, Gladys C.
AU - Sadagopan, Magesh
AU - Hayashizaki, Koji
AU - Takaku, Chiaki
AU - Tamanaka, Taichi
AU - Takematsu, Hiromu
AU - Kozutsumi, Yasunori
AU - Paulson, James C.
AU - Tsubata, Takeshi
AU - Ando, Hiromune
AU - Ishida, Hideharu
AU - Kiso, Makoto
N1 - Funding Information:
H.H.M.A. is grateful to the Egyptian Government for Ph.D. funding scholarship. This work was partly supported by the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan (Grant-in-Aid for Scientific Research to M. Kiso, Nos. 1710100 and 22380007 ) and CREST of JST (Japan Science and Technology Corporation) and NIH grants GM60938 and AI50143 to J. Paulson.
PY - 2011/3/15
Y1 - 2011/3/15
N2 - 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.
AB - 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.
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U2 - 10.1016/j.bmc.2011.01.060
DO - 10.1016/j.bmc.2011.01.060
M3 - Article
C2 - 21349726
AN - SCOPUS:79952450817
VL - 19
SP - 1966
EP - 1971
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 6
ER -