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2-C-Branced mannosides as a novel family of FimH antagonists - Synthesis and biological evaluation
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
 
ID 3707431
Author(s) Schönemann, Wojciech; Lindegger, Marcel; Rabbani, Said; Zihlmann, Pascal
Author(s) at UniBasel Ernst, Beat
Schönemann, Wojciech
Rabbani, Said
Zihlmann, Pascal
Year 2017
Title 2-C-Branced mannosides as a novel family of FimH antagonists - Synthesis and biological evaluation
Journal Perspectives in Science
Volume 11
Pages / Article-Number 53-61
Keywords Urinary tract infections; Uropathogenic Escherichia coli; FimH antagonists; Carbohydrate-recognition domain; 2-C-Branched carbohydrates
Abstract Urinary tract infections (UTIs), which are among the most prevalent bacterial infections worldwide, are mainly attributed to uropathogenic Escherichia coli (UPEC). Because of frequent antibiotic treatment, antimicrobial resistance constitutes an increasing therapeutic problem. Antagonists of the mannose-specific bacterial lectin FimH, a key protein mediating the adhesion of UPEC to human bladder cells, would offer an alternative anti-adhesive treatment strategy. In general, FimH antagonists consist of a mannose moiety and a wide range of lipophilic aglycones. Modifications of the mannose core led to a distinct drop in affinity. A visual inspection of the crystal structure of FimH revealed a previously unexplored cavity surrounded by Ile13, Phe142 and Asp140, which could be reached by functional groups in the equatorial 2-position of the mannose. Here, we describe the synthesis of 2- C -branched mannosides and evaluation of their pharmacodynamic properties. ITC experiments with the selected antagonists revealed a drastic enthalpy loss for all 2- C -branched antagonists, which, however, is partially compensated by an entropy gain. This supports the hypothesis that the target cavity is too small to accommodate 2- C -substituents.
Publisher Elsevier
ISSN/ISBN 2213-0209
edoc-URL http://edoc.unibas.ch/52932/
Full Text on edoc Available
Digital Object Identifier DOI 10.1016/j.pisc.2016.10.002
 
   

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