Improvement of Aglycone π-Stacking Yields Nanomolar to Sub-nanomolar FimH Antagonists |
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Authors: | Dr Wojciech Schönemann Dr Jonathan Cramer Tobias Mühlethaler Dr Brigitte Fiege Marleen Silbermann Dr Said Rabbani Dr Philipp Dätwyler Dr Pascal Zihlmann Dr Roman P Jakob Dr Christoph P Sager Dr Martin Smie?ko Dr Oliver Schwardt Prof?Dr Timm Maier Prof?Dr Beat Ernst |
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Affiliation: | 1. Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland;2. Department Biozentrum, Focal Area Structural Biology, University of Basel, Klingelbergstrasse 70, 4056 Basel, Switzerland |
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Abstract: | Antimicrobial 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 α-d -mannosides leads to compounds with perfect π–π 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 1H,15N-HSQC NMR analysis. Finally, fluorination improves pharmacokinetic parameters predictive for oral availability. |
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Keywords: | antibiotics drug design FimH antagonists urinary tract infections uropathogenic Escherichia coli |
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