8usm | pdb_00008usm

FmlH Lectin Domain UTI89 - AM4085

spinqualitylabelsall models 8usm, resolution 1.63Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8usm is a 2 chain structure with sequence from Escherichia coli. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.63Å Ligands: XC8 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function YDEQ_ECOLI Publication Abstract from PubMed 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 betaGal and betaGalNAc 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 IC(50) of 0.19 muM 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. Discovery of Orally Bioavailable FmlH Lectin Antagonists as Treatment for Urinary Tract Infections.,Maddirala AR, Tamadonfar K, Pinkner JS, Sanick D, Hultgren SJ, Janetka JW J Med Chem. 2024 Mar 14;67(5):3668-3678. doi: 10.1021/acs.jmedchem.3c02128. Epub , 2024 Feb 3. PMID:38308631 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA