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Target Selectivity of FimH Antagonists
Meike Scharenberg1, Oliver Schwardt, Said Rabbani
1Institute of Molecular Pharmacy, Pharmacenter, University of Basel , Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
Journal of Medicinal Chemistry
|October 24, 2012
Summary
Mannose-based FimH antagonists show promise for treating urinary tract infections (UTIs) by blocking bacterial adhesion. Studies confirm their high selectivity, indicating minimal risk of adverse effects from binding to human mannose receptors.
Area of Science:
- Microbiology
- Pharmacology
- Biochemistry
Background:
- Urinary tract infections (UTIs) are commonly caused by uropathogenic Escherichia coli (UPEC).
- FimH antagonists, targeting the FimH lectin on UPEC type 1 pili, are novel UTI therapeutics.
- Existing antagonists are α-d-mannosides, raising concerns about potential binding to human mannose receptors.
Purpose of the Study:
- To evaluate the selectivity of novel mannose-based FimH antagonists.
- To compare the binding affinities of FimH antagonists to both bacterial FimH and human mannose receptors.
- To assess the potential for off-target side effects of these UTI therapeutics.
Main Methods:
- Synthesized five distinct families of FimH antagonists.
- Measured binding affinities of antagonists to purified FimH.
- Assessed binding affinities to eight different human mannose receptors using established assays.
Main Results:
- FimH antagonists demonstrated a wide selectivity range, spanning approximately five orders of magnitude.
- No significant nonselective binding was observed for the tested FimH antagonists against human mannose receptors.
- The selectivity profile supports the therapeutic potential of these compounds for UTI treatment.
Conclusions:
- Mannose-based FimH antagonists exhibit high selectivity for bacterial FimH over human mannose receptors.
- This selectivity suggests a favorable safety profile, minimizing the risk of adverse effects.
- FimH antagonists are promising candidates for developing effective and safe UTI therapeutics.
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