FimH antagonists: structure-activity and structure-property relationships for biphenyl α-D-mannopyranosides.
ABSTRACT Urinary tract infections (UTIs) are caused primarily by uropathogenic Escherichia coli (UPEC), which encode filamentous surface-adhesive organelles called type 1 pili. FimH is located at the tips of these pili. The initial attachment of UPEC to host cells is mediated by the interaction of the carbohydrate recognition domain (CRD) of FimH with oligomannosides on urothelial cells. Blocking these lectins with carbohydrates or analogues thereof prevents bacterial adhesion to host cells and therefore offers a potential therapeutic approach for prevention and/or treatment of UTIs. Although numerous FimH antagonists have been developed so far, few of them meet the requirement for clinical application due to poor pharmacokinetics. Additionally, the binding mode of an antagonist to the CRD of FimH can switch from an in-docking mode to an out-docking mode, depending on the structure of the antagonist. In this communication, biphenyl α-D-mannosides were modified to improve their binding affinity, to explore their binding mode, and to optimize their pharmacokinetic properties. The inhibitory potential of the FimH antagonists was measured in a cell-free competitive binding assay, a cell-based flow cytometry assay, and by isothermal titration calorimetry. Furthermore, pharmacokinetic properties such as log D, solubility, and membrane permeation were analyzed. As a result, a structure-activity and structure-property relationships were established for a series of biphenyl α-D-mannosides.
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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.ChemMedChem 12/2013; · 3.05 Impact Factor
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ABSTRACT: Dendritic cell-specific, intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) is a C-type lectin expressed specifically on dendritic cells. It is a primary site for recognition and binding of various pathogens and thus a promising therapeutic target for inhibition of pathogen entry and subsequent prevention of immune defense cell infection. We report the design and synthesis of d-mannose-based DC-SIGN antagonists bearing diaryl substituted 1,3-diaminopropanol or glycerol moieties incorporated to target the hydrophobic groove of the receptor. The designed glycomimetics were evaluated by in vitro assay of the isolated DC-SIGN extracellular domain for their ability to compete with HIV-1 gp120 for binding to the DC-SIGN carbohydrate recognition domain. Compounds 14d and 14e, that display IC50 values of 40 μM and 50 μM, are among the most potent monovalent DC-SIGN antagonists reported. The antagonistic effect of all the synthesized compounds was further evaluated by a one-point in vitro assay that measures DC adhesion. Compounds 14d, 14e, 18d and 18e were shown to act as functional antagonists of DC-SIGN-mediated DC adhesion. The binding mode of 14d was also studied by molecular docking and molecular dynamics simulation, which revealed flexibility of 14d in the binding site and provides a basis for further optimization.European Journal of Medicinal Chemistry 03/2014; 75:308–326. · 3.43 Impact Factor
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ABSTRACT: Just like bacteria need to be mobile to seek for nutrients, bacteria need to adhere to biotic and abiotic surfaces to enable their progression. Most bacteria regulate the expression of a multitude of fimbrial adhesins that display varying specificities and architectures. FimH at the tip of type 1 fimbriae is one of the first recognized lectins on Escherichia coli. FimH evokes through its binding symptomatic and chronic E. coli infections in the urinary tract, in the intestine, and beyond. The mannose specificity of type 1 fimbriae has been the lead to the discovery of the FimH adhesin more than 32 years ago and presents today a role model as the template for anti-adhesive drug design. Curiously, the specificity of the FimH lectin had been defined very early on toward a Manα1,3Manβ1,4GlcNAc trisaccharide isolated from the urine of mannosidase-deficient patients. Indeed, a much larger dependence of bacterial adhesion can be attributed to structural differences in the mannosidic receptors than based on amino acid variance in FimH. The crystal structure of FimH in complex with oligomannoside-3 presented a breakthrough that enhanced the rational design of mannose-based anti-adhesives against FimH. In this overview, we will provide insights gained from a plethora of FimH antagonists. Crystal structures of FimH in complex with anti-adhesives and applications in vivo in mouse models for metabolic diseases reveal unexpected features and alternative routes for improved molecules.Top Med Chem, 2014 edited by Dr. Peter H. Seeberger, Dr. Christoph Rademacher, 08/2014: chapter 52; Springer-Verlag Berlin Heidelberg.