化学
生物利用度
药代动力学
药理学
口服
大肠杆菌
苷元
连接器
糖苷
立体化学
生物化学
医学
操作系统
基因
计算机科学
作者
Amarendar Reddy Maddirala,Jerome S. Pinkner,Kevin O. Tamadonfar,Denise Sanick,Scott J. Hultgren,James W. Janetka
标识
DOI:10.1021/acs.jmedchem.3c02128
摘要
FmlH, a bacterial adhesin of uropathogenic Escherichia coli (UPEC), has been shown to provide a fitness advantage in colonizing the bladder during chronic urinary tract infections (UTIs). Previously reported ortho-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 69 with an IC50 of 0.19 μM against FmlH and 53% oral bioavailability in mice. We also obtained a FimlH-bound X-ray structure of lead compound 69 (AM4085) which has potential as a new antivirulence therapeutic for UTIs.
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