Kinetic Properties of Carbohydrate–Lectin Interactions: FimH Antagonists |
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Authors: | Dr Meike Scharenberg Dr Xiaohua Jiang Lijuan Pang Giulio Navarra Dr Said Rabbani Dr Florian Binder Dr Oliver Schwardt Prof?Dr Beat Ernst |
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Affiliation: | Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, 4056 Basel (Switzerland) |
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Abstract: | The lectin FimH is terminally expressed on type 1 pili of uropathogenic Escherichia coli (UPEC), which is the main cause of urinary tract infections (UTIs). FimH enables bacterial adhesion to urothelial cells, the initial step of infection. Various mannose derivatives have been shown to antagonize FimH and are therefore considered to be promising therapeutic agents for the treatment of UTIs. As part of the preclinical development process, when the kinetic properties of FimH antagonists were examined by surface plasmon resonance, extremely low dissociation rates (koff) were found, which is uncommon for carbohydrate–lectin interactions. As a consequence, the corresponding half‐lives (t1/2) of the FimH antagonist complexes are above 3.6 h. For a therapeutic application, extended t1/2 values are a prerequisite for success, since the target occupancy time directly influences the in vivo drug efficacy. The long t1/2 value of the tested FimH antagonists further confirms their drug‐like properties and their high therapeutic potential. |
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Keywords: | antagonists carbohydrate– lectin interactions FimH kinetics urinary tract infections uropathogenic Escherichia coli |
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