6g2s
Crystal structure of FimH in complex with a pentaflourinated biphenyl alpha D-mannosideCrystal structure of FimH in complex with a pentaflourinated biphenyl alpha D-mannoside
Structural highlights
Function[FIMH_ECOLI] Involved in regulation of length and mediation of adhesion of type 1 fimbriae (but not necessary for the production of fimbriae). Adhesin responsible for the binding to D-mannose. It is laterally positioned at intervals in the structure of the type 1 fimbriae. In order to integrate FimH in the fimbriae FimF and FimG are needed. Publication Abstract from PubMedAntimicrobial resistance has become a serious concern for the treatment of urinary tract infections. In this context, an anti-adhesive approach targeting FimH, a bacterial lectin enabling the attachment of E. coli to host cells, has attracted considerable interest. FimH can adopt a low/medium-affinity state in the absence and a high-affinity state in the presence of shear forces. Until recently, mostly the high-affinity state has been investigated, despite the fact that a therapeutic antagonist should bind predominantly to the low-affinity state. In this communication, we demonstrate that fluorination of biphenyl alpha-d-mannosides leads to compounds with perfect pi-pi stacking interactions with the tyrosine gate of FimH, yielding low nanomolar to sub-nanomolar KD values for the low- and high-affinity states, respectively. The face-to-face alignment of the perfluorinated biphenyl group of FimH ligands and Tyr48 was confirmed by crystal structures as well as (1) H,(15) N-HSQC NMR analysis. Finally, fluorination improves pharmacokinetic parameters predictive for oral availability. Improvement of Aglycone pi-Stacking Yields Nanomolar to Sub-nanomolar FimH Antagonists.,Schonemann W, Cramer J, Muhlethaler T, Fiege B, Silbermann M, Rabbani S, Datwyler P, Zihlmann P, Jakob RP, Sager CP, Smiesko M, Schwardt O, Maier T, Ernst B ChemMedChem. 2019 Feb 1. doi: 10.1002/cmdc.201900051. PMID:30710416[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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