Structure-based drug design and optimization of mannoside bacterial FimH antagonists.
Structure-based drug design and optimization of mannoside bacterial FimH antagonists.
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DOI：
10.1021/jm100438s
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发表时间：
2010-06-24
影响因子：
7.3
通讯作者：
Janetka JW
中科院分区：
文献类型：
--
作者：
Han Z;Pinkner JS;Ford B;Obermann R;Nolan W;Wildman SA;Hobbs D;Ellenberger T;Cusumano CK;Hultgren SJ;Janetka JW
FimH介导的细胞与甘露糖基化蛋白的粘附在致尿路感染大肠杆菌的能力中至关重要。大肠埃希菌（UPEC）在尿路感染过程中定植并侵入膀胱上皮。我们描述了使用X射线结构指导的药物设计，发现和优化基于α-D-甘露糖1-位异头糖苷的有效小分子FimH细菌粘附拮抗剂。优化的联芳基甘露糖苷在荧光偏振测定中显示出对FimH的低纳摩尔结合亲和力，并且在细菌粘附的血凝（HA）功能细胞测定中显示出亚微摩尔细胞活性。X射线晶体学表明，联苯部分与FimH的外表面产生几种关键的相互作用，包括与Tyr-48的π-π相互作用和与Arg-98/Glu-50盐桥的氢键静电相互作用。通过联芳环连接的二聚体类似物显示出相对于单体匹配对的效力令人印象深刻的8倍增加，并且代表迄今为止鉴定的最有效的FimH拮抗剂。本文所述的FimH拮抗剂作为有效治疗尿路感染的新型治疗剂具有巨大的开发潜力。
FimH-mediated cellular adhesion to mannosylated proteins is critical in the ability of uropathogenic E. coli (UPEC) to colonize and invade the bladder epithelium during urinary tract infection. We describe the discovery and optimization of potent small-molecule FimH bacterial adhesion antagonists based on α-D-mannose 1-position anomeric glycosides using X-ray structure-guided drug design. Optimized biaryl mannosides display low nanomolar binding affinity for FimH in a fluorescence polarization assay and sub micromolar cellular activity in a hemagglutination (HA) functional cell assay of bacterial adhesion. X-ray crystallography demonstrates that the biphenyl moiety makes several key interactions with the outer surface of FimH including π-π interactions with Tyr-48 and an H-bonding electrostatic interaction with the Arg-98/Glu-50 salt-bridge. Dimeric analogs linked through the biaryl ring show an impressive 8-fold increase in potency relative to monomeric matched pairs and represent the most potent FimH antagonists identified to date. The FimH antagonists described herein hold great potential for development as novel therapeutics for the effective treatment of urinary tract infections.
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DOI：
10.1107/s0907444909029436
发表时间：
2009-10-01
影响因子：
2.2
作者：
Moriarty, Nigel W.;Grosse-Kunstleve, Ralf W.;Adams, Paul D.
通讯作者：
Adams, Paul D.
影响因子：
3.4
作者：
Gouin, Sebastien G.;Wellens, Adinda;Kovensky, Jose
通讯作者：
Kovensky, Jose
影响因子：
3
作者：
Lindhorst, TK;Kieburg, C;Krallmann-Wenzel, U
通讯作者：
Krallmann-Wenzel, U
影响因子：
1.8
作者：
MEUWLY, R;VASELLA, A
通讯作者：
VASELLA, A
影响因子：
64.8
作者：
ABRAHAM, SN;SUN, DX;BEACHEY, EH
通讯作者：
BEACHEY, EH