CD22-antagonists with nanomolar potency: the synergistic effect of hydrophobic groups at C-2 and C-9 of sialic acid scaffold.
CD22-antagonists with nanomolar potency: the synergistic effect of hydrophobic groups at C-2 and C-9 of sialic acid scaffold.
复制标题
DOI：
10.1016/j.bmc.2011.01.060
复制
发表时间：
2011-03-15
影响因子：
3.5
通讯作者：
Kiso, Makoto
中科院分区：
文献类型：
--
作者：
Abdu-Allah, Hajjaj H. M.;Watanabe, Kozo;Completo, Gladys C.;Sadagopan, Magesh;Hayashizaki, Koji;Takaku, Chiaki;Tamanaka, Taichi;Takematsu, Hiromu;Kozutsumi, Yasunori;Paulson, James C.;Tsubata, Takeshi;Ando, Hiromune;Ishida, Hideharu;Kiso, Makoto
在早期的研究中，我们鉴定了C-9氨基衍生物1（9-（4 '-羟基-4-联苯基）乙酰氨基-9-脱氧-Neu 5Gc α2- 6 GalOMP）和C-9氨基衍生物2（9-（4'-羟基-4-联苯基）甲基氨基-9-脱氧-Neu 5Gc α2- 6 GalOMP）分别对小鼠CD 22和人CD 22具有最有希望的亲和力。用苄基（5）或联苯甲基（6）作为糖苷配基取代1的亚末端半乳糖残基（2- 6 Gal-OMP）导致mCD 22的甚至更高的效力。在该研究中，两种化合物均显示出对CD 22的改善的效力和选择性（IC 50 70 nM），并且对CD 22的选择性比对MAG的选择性高712倍。2的相应衍生物，化合物8和9，显示出与2相当的活性，但比5和6的效力和选择性低。虽然化合物5-9是简单的小分子量拮抗剂，但它们显示出比具有α 2- 6 Gal连接的相应化合物高得多的效力和选择性。生物学和计算对接模拟研究表明，1和2的2- 6 Gal-OMP残基对于结合过程不是关键的，并且可以被疏水性非碳水化合物部分取代。本文提供的数据对下一代CD 22拮抗剂的设计和发现具有重要意义
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
登录
查看更多内容
影响因子：
7.3
作者：
Abdui-Allah, Hajaj H. M.;Tainanaka, Taichi;Kiso, Makoto
通讯作者：
Kiso, Makoto
影响因子：
5.3
作者：
Naito, Yuko;Takematsu, Hiromu;Kozutsumi, Yasunori
通讯作者：
Kozutsumi, Yasunori
DOI：
10.1046/j.1432-1327.1998.2550663.x
发表时间：
1998-08-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Kelm, S;Brossmer, R;Schauer, R
通讯作者：
Schauer, R
影响因子：
4.4
作者：
Onodera, Taishi;Poe, Jonathan C.;Tsubata, Takeshi
通讯作者：
Tsubata, Takeshi
影响因子：
3.5
作者：
Shelke, Sachin V.;Gao, Gan-Pan;Ernst, Beat
通讯作者：
Ernst, Beat