Mannose-based FimH antagonists are considered new therapeutics for the treatment of urinary tract infections (UTIs). They prevent the adhesion of uropathogenic Escherichia coli (UPEC) to urothelial cell surfaces triggered by the lectin FimH, which is located at the tip of bacterial type 1 pili. Because all reported FimH antagonists are α-d-mannosides, they are also potential ligands of mannose receptors of the human host system. We therefore investigated the selectivity range of five FimH antagonists belonging to different compound families by comparing their affinities for FimH and eight human mannose receptors. On the basis of the detected selectivity range of approximately 5 orders of magnitude, no adverse side effects resulting from nonselective binding to the human receptors have to be expected. FimH antagonists can therefore be further considered as potential therapeutics for the treatment of UTI.
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http://dx.doi.org/10.1021/jm3010338 | DOI Listing |
ACS Med Chem Lett
October 2024
State Key Laboratory of Applied Organic Chemistry, Department of Chemistry and School of Pharmacy, Lanzhou University, Lanzhou 730000, P. R. China.
Synthesizing FimH antagonists is challenging because of their densely functionalized and stereochemically complex -mannoside structures, resulting in low yields and lengthy processes. We present an efficient method for synthesizing -mannoside FimH antagonists by nickel-catalyzed reductive coupling and stereocontrolled reduction, thereby significantly simplifying the process and enabling the synthesis of FimH antagonists in just four steps with an overall yield of 34-50%. This efficient synthesis holds significant potential for the rapid development of analogues targeting the treatment of urinary tract infections or Crohn's disease caused by ().
View Article and Find Full Text PDFProc Natl Acad Sci U S A
September 2024
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110.
is an important pathogen causing difficult-to-treat urinary tract infections (UTIs). Over 1.5 million women per year suffer from recurrent UTI, reducing quality of life and causing substantial morbidity and mortality, especially in the hospital setting.
View Article and Find Full Text PDFBioorg Chem
April 2024
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt. Electronic address:
FimH is a mannose-recognizing lectin that is expressed by Escherichia coli guiding its ability to adhere and infect cells. It is involved in pathogenesis of urinary tract infections and Chron's disease. Several X-ray structure-guided ligand design studies were extensively utilized in the discovery and optimization of small molecule aryl mannoside FimH antagonists.
View Article and Find Full Text PDFEur J Med Chem
March 2024
Department of Chemistry, University of Connecticut, 55 North Eagleville Road, U3060, Storrs, CT, 06269, USA. Electronic address:
The pharmacological modulation of disease-relevant carbohydrate-protein interactions represents an underexplored area of medicinal chemistry. One particular challenge in the design of glycomimetic compounds is the inherent instability of the glycosidic bond toward enzymatic cleavage. This problem has traditionally been approached by employing S-, N-, or C-glycosides with reduced susceptibility toward glycosidases.
View Article and Find Full Text PDFJ Biol Chem
May 2023
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF), UMR 8576 CNRS and University of Lille, Villeneuve d'Ascq, France. Electronic address:
The FimH type-1 fimbrial adhesin allows pathogenic Escherichia coli to adhere to glycoproteins in the epithelial linings of human bladder and intestinal tract, by using multiple fimbriae simultaneously. Pauci- and high-mannose type N-glycans are natural FimH receptors on those glycoproteins. Oligomannose-3 and oligomannose-5 bind with the highest affinity to FimH by using the same Manα1,3Man branch.
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