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Online ISSN: 1860-7187
May 30, 2012
VIP: 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*
Urinary tract infections (UTIs), caused primarily by uropathogenic E. coli (UPEC), affect millions of people and account for significant morbidity and high medical costs. UPEC strains 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 interactions between the carbohydrate recognition domain (CRD) of FimH and oligomannosides on urothelial cells. Blocking these lectins with carbohydrates or analogues thereof prevents bacterial adhesion to host cells, offering a potential therapeutic approach for the prevention and treatment of UTIs. Although numerous FimH antagonists have been developed, few of them meet requirements for clinical application due to poor pharmacokinetic properties. Moreover, 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 antagonist's structure.
Beat Ernst and his colleagues at the University of Basel in Switzerland synthesized a series of biphenyl α-D-mannosides as FimH antagonists with the aim of improving binding affinity and optimizing pharmacokinetic properties. The inhibitory potential of the FimH antagonists was measured in a cell-free competitive binding assay, a cell-based flow cytometry assay, as well as by isothermal titration calorimetry (ITC). Furthermore, pharmacokinetic properties such as logD, solubility, and permeation through membranes were analyzed. As a result, a structure–activity relationship (SAR) and a structure–property relationship (SPR) were established for a series of biphenyl α-D-mannosides.
Received March 6, 2012; published online May 29, 2012, DOI: 10.1002/cmdc.201200125.