FimH Antagonists: Structure–Activity and Structure–Property Relationships for Biphenyl α‐D‐Mannopyranosides
FimH Antagonists: Structure–Activity and Structure–Property Relationships for Biphenyl α‐D‐Mannopyranosides
复制标题
FimH 拮抗剂：联苯 α-D-吡喃甘露糖苷的结构-活性和结构-性质关系
作者：
L. Pang;Simon Kleeb;Katrin Lemme;S. Rabbani;M. Scharenberg;Adam Zalewski;Florentina Schädler;O. Schwardt;B. Ernst
尿路感染（UTI）主要由尿路致病性大肠杆菌（UPEC）引起，其编码称为1型皮利的丝状表面粘附细胞器。 FimH位于这些皮利的尖端。UPEC与宿主细胞的初始附着是由FimH的碳水化合物识别结构域（CRD）与尿路上皮细胞上的寡甘露糖苷的相互作用介导的。用碳水化合物或其类似物阻断这些凝集素可防止细菌粘附于宿主细胞，因此为预防和/或治疗UTI提供了潜在的治疗方法。尽管迄今为止已经开发了许多FimH拮抗剂，但由于药代动力学较差，很少有药物满足临床应用的要求。此外，拮抗剂与FimH的CRD的结合模式可以从入对接模式转换为出对接模式，这取决于拮抗剂的结构。在本通讯中，联苯α-D-甘露糖苷被修饰以提高其结合亲和力，探索其结合模式，并优化其药代动力学性质。在无细胞竞争性结合试验、基于细胞的流式细胞术试验和等温滴定量热法中测量FimH拮抗剂的抑制潜力。此外，分析了药物动力学特性，如log D、溶解度和膜渗透。建立了一系列联苯型α-D-甘露糖苷类化合物的构效关系和构效关系。
Urinary tract infections (UTIs) are caused primarily by uropathogenic Escherichia coli (UPEC), which encode filamentous surface‐adhesive organelles called type 1 pili. FimH is located at the tips of these pili. The initial attachment of UPEC to host cells is mediated by the interaction of the carbohydrate recognition domain (CRD) of FimH with oligomannosides on urothelial cells. Blocking these lectins with carbohydrates or analogues thereof prevents bacterial adhesion to host cells and therefore offers a potential therapeutic approach for prevention and/or treatment of UTIs. Although numerous FimH antagonists have been developed so far, few of them meet the requirement for clinical application due to poor pharmacokinetics. Additionally, the binding mode of an antagonist to the CRD of FimH can switch from an in‐docking mode to an out‐docking mode, depending on the structure of the antagonist. In this communication, biphenyl α‐D‐mannosides were modified to improve their binding affinity, to explore their binding mode, and to optimize their pharmacokinetic properties. The inhibitory potential of the FimH antagonists was measured in a cell‐free competitive binding assay, a cell‐based flow cytometry assay, and by isothermal titration calorimetry. Furthermore, pharmacokinetic properties such as log D, solubility, and membrane permeation were analyzed. As a result, a structure–activity and structure–property relationships were established for a series of biphenyl α‐D‐mannosides.
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影响因子：
120.1
作者：
Ladbury, John E.;Klebe, Gerhard;Freire, Ernesto
通讯作者：
Freire, Ernesto
影响因子：
7.3
作者：
Han Z;Pinkner JS;Ford B;Obermann R;Nolan W;Wildman SA;Hobbs D;Ellenberger T;Cusumano CK;Hultgren SJ;Janetka JW
通讯作者：
Janetka JW
影响因子：
56.9
作者：
Choudhury, D;Thompson, A;Knight, SD
通讯作者：
Knight, SD
影响因子：
7.4
作者：
Freire, Ernesto
通讯作者：
Freire, Ernesto