Lijuan Pang

Publications (2)7.95 Total impact

• Article: FimH antagonists: structure-activity and structure-property relationships for biphenyl α-D-mannopyranosides.

  Lijuan Pang, Simon Kleeb, Katrin Lemme, Said Rabbani, Meike Scharenberg, Adam Zalewski, Florentina Schädler, Oliver Schwardt, Beat Ernst
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  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.
  ChemMedChem 05/2012; 7(8):1404-22. · 3.15 Impact Factor
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  Available from: unibas.ch

  Article: FimH antagonists for the oral treatment of urinary tract infections: from design and synthesis to in vitro and in vivo evaluation.

  Tobias Klein, Daniela Abgottspon, Matthias Wittwer, Said Rabbani, Janno Herold, Xiaohua Jiang, Simon Kleeb, Christine Lüthi, Meike Scharenberg, Jacqueline Bezençon, Erich Gubler, Lijuan Pang, Martin Smiesko, Brian Cutting, Oliver Schwardt, Beat Ernst
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  ABSTRACT: Urinary tract infection (UTI) by uropathogenic Escherichia coli (UPEC) is one of the most common infections, particularly affecting women. The interaction of FimH, a lectin located at the tip of bacterial pili, with high mannose structures is critical for the ability of UPEC to colonize and invade the bladder epithelium. We describe the synthesis and the in vitro/in vivo evaluation of α-D-mannosides with the ability to block the bacteria/host cell interaction. According to the pharmacokinetic properties, a prodrug approach for their evaluation in the UTI mouse model was explored. As a result, an orally available, low molecular weight FimH antagonist was identified with the potential to reduce the colony forming units (CFU) in the urine by 2 orders of magnitude and in the bladder by 4 orders of magnitude. With FimH antagonist, the great potential for the effective treatment of urinary tract infections with a new class of orally available antiinfectives could be demonstrated.
  Journal of Medicinal Chemistry 12/2010; 53(24):8627-41. · 4.80 Impact Factor