4CST

Crystal structure of FimH in complex with 3'-Chloro-4'-(alpha-D-mannopyranosyloxy)-biphenyl-4-carbonitrile

4CST の概要

• エントリーDOI: 10.2210/pdb4cst/pdb
• 関連するPDBエントリー: 4CSS 4CSY
• 分子名称: PROTEIN FIMH, 3'-chloro-4'-(alpha-D-mannopyranosyloxy)biphenyl-4-carbonitrile (3 entities in total)
• 機能のキーワード: sugar binding protein, fimh antagonists, type i pili, uti, upec, adhesin
• 由来する生物種: ESCHERICHIA COLI K-12
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 17832.28

構造登録者

Kleeb, S.,Pang, L.,Mayer, K.,Sigl, A.,Eris, D.,Preston, R.C.,Zihlmann, P.,Abgottspon, D.,Hutter, A.,Scharenberg, M.,Jian, X.,Navarra, G.,Rabbani, S.,Smiesko, M.,Luedin, N.,Jakob, R.P.,Schwardt, O.,Maier, T.,Sharpe, T.,Ernst, B. (登録日: 2014-03-10, 公開日: 2015-02-25, 最終更新日: 2024-11-13)

主引用文献

Ernst, B.,Kleeb, S.,Pang, L.,Mayer, K.,Eris, D.,Sigl, A.,Zihlmann, P.,Preston, R.C.,Sharpe, T.,Jakob, R.,Abgottspon, D.,Hutter, A.S.,Scharenberg, M.,Jiang, X.,Navarra, G.,Rabbani, S.,Smiesko, M.,Ludin, N.,Bezencon, J.,Schwardt, O.,Maier, T.
Fimh Antagonists: Bioisosteres to Improve the in Vitro and in Vivo Pk/Pd Profile.
J.Med.Chem., 58:2221-, 2015

PubMed Abstract: Urinary tract infections (UTIs), predominantly caused by uropathogenic Escherichia coli (UPEC), belong to the most prevalent infectious diseases worldwide. The attachment of UPEC to host cells is mediated by FimH, a mannose-binding adhesin at the tip of bacterial type 1 pili. To date, UTIs are mainly treated with antibiotics, leading to the ubiquitous problem of increasing resistance against most of the currently available antimicrobials. Therefore, new treatment strategies are urgently needed. Here, we describe the development of an orally available FimH antagonist. Starting from the carboxylate substituted biphenyl α-d-mannoside 9, affinity and the relevant pharmacokinetic parameters (solubility, permeability, renal excretion) were substantially improved by a bioisosteric approach. With 3'-chloro-4'-(α-d-mannopyranosyloxy)biphenyl-4-carbonitrile (10j) a FimH antagonist with an optimal in vitro PK/PD profile was identified. Orally applied, 10j was effective in a mouse model of UTI by reducing the bacterial load in the bladder by about 1000-fold.

PubMed: 25666045
DOI: 10.1021/JM501524Q

実験手法

X-RAY DIFFRACTION (1.1 Å)