8USM

FmlH Lectin Domain UTI89 - AM4085

8USM の概要

• エントリーDOI: 10.2210/pdb8usm/pdb
• 分子名称: Fimbrial protein (Fragment), 4'-fluoro-6-(trifluoromethyl)[1,1'-biphenyl]-2-yl 2-acetamido-2-deoxy-beta-D-galactopyranoside (3 entities in total)
• 機能のキーワード: adhesin inhibitor, cell adhesion
• 由来する生物種: Escherichia coli
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 36758.95

構造登録者

Tamadonfar, K.O.,Pinkner, J.P.,Maddirala, A.R.,Janetka, J.W.,Hultgren, S.J. (登録日: 2023-10-27, 公開日: 2024-02-14, 最終更新日: 2024-11-06)

主引用文献

Maddirala, A.R.,Tamadonfar, K.,Pinkner, J.S.,Sanick, D.,Hultgren, S.J.,Janetka, J.W.
Discovery of Orally Bioavailable FmlH Lectin Antagonists as Treatment for Urinary Tract Infections.
J.Med.Chem., 67:3668-3678, 2024

PubMed Abstract: FmlH, a bacterial adhesin of uropathogenic (UPEC), has been shown to provide a fitness advantage in colonizing the bladder during chronic urinary tract infections (UTIs). Previously reported -biphenyl glycosides based on βGal and βGalNAc have excellent binding affinity to FmlH and potently block binding to its natural carbohydrate receptor, but they lack oral bioavailability. In this paper, we outline studies where we have optimized compounds for improved pharmacokinetics, leading to the discovery of novel analogues with good oral bioavailability. We synthesized galactosides with the anomeric O-linker replaced with more stable S- and C-linked linkers. We also investigated modifications to the GalNAc sugar and modifications to the biphenyl aglycone. We identified GalNAc with an IC of 0.19 μM against FmlH and 53% oral bioavailability in mice. We also obtained a FimlH-bound X-ray structure of lead compound (AM4085) which has potential as a new antivirulence therapeutic for UTIs.

PubMed: 38308631
DOI: 10.1021/acs.jmedchem.3c02128

実験手法

X-RAY DIFFRACTION (1.63 Å)