5F2F

Crystal structure of para-biphenyl-2-methyl-3', 5' di-methyl amide mannoside bound to FimH lectin domain

5F2F の概要

• エントリーDOI: 10.2210/pdb5f2f/pdb
• 分子名称: Protein FimH, 5-[4-[(2~{R},3~{S},4~{S},5~{S},6~{R})-6-(hydroxymethyl)-3,4,5-tris(oxidanyl)oxan-2-yl]oxy-3-methyl-phenyl]-~{N}1,~{N}3-dimethyl-benzene-1,3-dicarboxamide, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: lectin, mannoside, immunoglobulin fold, carbohydrate binding protein, sugar binding protein
• 由来する生物種: Escherichia coli J96
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 17561.49

構造登録者

Kalas, V.,Hultgren, S.J. (登録日: 2015-12-01, 公開日: 2016-05-04, 最終更新日: 2024-10-16)

主引用文献

Jarvis, C.,Han, Z.,Kalas, V.,Klein, R.,Pinkner, J.S.,Ford, B.,Binkley, J.,Cusumano, C.K.,Cusumano, Z.,Mydock-McGrane, L.,Hultgren, S.J.,Janetka, J.W.
Antivirulence Isoquinolone Mannosides: Optimization of the Biaryl Aglycone for FimH Lectin Binding Affinity and Efficacy in the Treatment of Chronic UTI.
Chemmedchem, 11:367-373, 2016

PubMed Abstract: Uropathogenic E. coli (UPEC) employ the mannose-binding adhesin FimH to colonize the bladder epithelium during urinary tract infection (UTI). Previously reported FimH antagonists exhibit good potency and efficacy, but low bioavailability and a short half-life in vivo. In a rational design strategy, we obtained an X-ray structure of lead mannosides and then designed mannosides with improved drug-like properties. We show that cyclizing the carboxamide onto the biphenyl B-ring aglycone of biphenyl mannosides into a fused heterocyclic ring, generates new biaryl mannosides such as isoquinolone 22 (2-methyl-4-(1-oxo-1,2-dihydroisoquinolin-7-yl)phenyl α-d-mannopyranoside) with enhanced potency and in vivo efficacy resulting from increased oral bioavailability. N-Substitution of the isoquinolone aglycone with various functionalities produced a new potent subseries of FimH antagonists. All analogues of the subseries have higher FimH binding affinity than unsubstituted lead 22, as determined by thermal shift differential scanning fluorimetry assay. Mannosides with pyridyl substitution on the isoquinolone group inhibit bacteria-mediated hemagglutination and prevent biofilm formation by UPEC with single-digit nanomolar potency, which is unprecedented for any FimH antagonists or any other antivirulence compounds reported to date.

PubMed: 26812660
DOI: 10.1002/cmdc.201600006

実験手法

X-RAY DIFFRACTION (1.665 Å)