A5080896513- Glycosylation and Glycoproteins Research
- Carbohydrate Chemistry and Synthesis
- Escherichia coli research studies
- Antibiotic Resistance in Bacteria
- Chemical Synthesis and Analysis
- Urinary Tract Infections Management
- Monoclonal and Polyclonal Antibodies Research
- Click Chemistry and Applications
- Cell Adhesion Molecules Research
- Signaling Pathways in Disease
- Galectins and Cancer Biology
- Enzyme Production and Characterization
- Synthesis and Characterization of Heterocyclic Compounds
- Computational Drug Discovery Methods
- Synthesis and Reactions of Organic Compounds
- Bacteriophages and microbial interactions
- Lipid Membrane Structure and Behavior
- Axon Guidance and Neuronal Signaling
- Crystallography and molecular interactions
- Microbial Natural Products and Biosynthesis
- Protein Structure and Dynamics
- Immunotherapy and Immune Responses
- Antimicrobial Peptides and Activities
- Synthesis of Organic Compounds
- Nerve injury and regeneration
University of Basel
2013-2024
Novartis (Switzerland)
2001-2009
Klinikum Görlitz
2007
University of Stuttgart
1996-2006
Institut de Chimie des Substances Naturelles
1997
Centre National de la Recherche Scientifique
1997
Urinary tract infection (UTI) by uropathogenic Escherichia coli (UPEC) is one of the most common infections, particularly affecting women. The interaction FimH, a lectin located at tip bacterial pili, with high mannose structures critical for ability UPEC to colonize and invade bladder epithelium. We describe synthesis in vitro/in vivo evaluation α-d-mannosides block bacteria/host cell interaction. According pharmacokinetic properties, prodrug approach their UTI mouse model was explored. As...
The initial step for the successful establishment of urinary tract infections (UTIs), predominantly caused by uropathogenic Escherichia coli, is adhesion bacteria to urothelial cells. This attachment mediated FimH, a mannose-binding adhesin, which expressed on bacterial surface. To date, UTIs are mainly treated with antibiotics, leading ubiquitous problem increasing resistance against most currently available antimicrobials. Therefore, new treatment strategies urgently needed, avoiding...
Urinary tract infections (UTIs), predominantly caused by uropathogenic Escherichia coli (UPEC), belong to the most prevalent infectious diseases worldwide. The attachment of UPEC host cells is mediated FimH, a mannose-binding adhesin at tip bacterial type 1 pili. To date, UTIs are mainly treated with antibiotics, leading ubiquitous problem increasing resistance against currently available antimicrobials. Therefore, new treatment strategies urgently needed. Here, we describe development an...
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 The initial attachment UPEC to host cells mediated interaction carbohydrate recognition domain (CRD) with oligomannosides on urothelial cells. Blocking lectins carbohydrates or analogues thereof prevents bacterial adhesion and therefore offers a potential therapeutic approach for prevention...
The C-type lectin receptor DC-SIGN is a pattern recognition expressed on macrophages and dendritic cells. It has been identified as promiscuous entry for many pathogens, including epidemic pandemic viruses such SARS-CoV-2, Ebola virus, HIV-1. In the context of recent SARS-CoV-2 pandemic, DC-SIGN-mediated virus dissemination stimulation innate immune responses implicated potential factor in development severe COVID-19. Inhibition binding to DC-SIGN, thus, represents an attractive...
Selectins, a family of C-type lectins, play key role in inflammatory diseases (e.g., asthma and arthritis). However, the only millimolar affinity sialyl Lewisx (sLex), which is common tetrasaccharide epitope all physiological selectin ligands, has been major obstacle to development antagonists for therapeutic applications. In fragment-based approach guided by NMR, ligands binding second site close proximity sLex mimic were identified. A library obtained connecting best second-site ligand via...
Mannose-based FimH antagonists are considered new therapeutics for the treatment of urinary tract infections (UTIs). They prevent adhesion uropathogenic Escherichia coli (UPEC) to urothelial cell surfaces triggered by lectin FimH, which is located at tip bacterial type 1 pili. Because all reported α-d-mannosides, they also potential ligands mannose receptors human host system. We therefore investigated selectivity range five belonging different compound families comparing their affinities...
Urinary tract infections caused by uropathogenic E. coli are among the most prevalent infectious diseases. The mannose-specific lectin FimH mediates adhesion of bacteria to urothelium, thus enabling host cell invasion and recurrent infections. An attractive alternative antibiotic treatment is development antagonists that mimic physiological ligand. A large variety candidate drugs have been developed characterized means in vitro studies animal models. Here we present X-ray co-crystal...
The widespread occurrence of urinary tract infections has resulted in frequent antibiotic treatment, contributing to the emergence antimicrobial resistance. Alternative approaches are therefore required. In initial step colonization, FimH, a lectin located at tip bacterial type 1 pili, interacts with mannosylated glycoproteins on urothelial mucosa. This pathogen/host interaction is efficiently antagonized by biaryl α-d-mannopyranosides. However, their poor physicochemical properties,...
In the lead: The title method for identification of ligands is particularly useful binding sites where little or no structural information available. a fragment-based approach, suitable pair first- and second-site identified by NMR experiments. By applying receptor-mediated in situ combinatorial two are then linked to generate new high-affinity lead structure (see picture).
Siglec-2, also known as CD22, is involved in the regulation and survival of B-cells has been successfully targeted cell depletion therapies with antibody-based approaches. Sialic acid derivatives, already to bind high affinity myelin-associated glycoprotein (MAG, Siglec-4), were screened for their binding CD22 by surface plasmon resonance. The best compound identified was further modified various hydrophobic substituents at 2-, 5-, 9-positions sialic scaffold, leading nanomolar which ligand...
Abstract Antimicrobial resistance has become a serious concern for the treatment of urinary tract infections. In this context, an anti‐adhesive approach targeting FimH, bacterial lectin enabling attachment E. coli to host cells, attracted considerable interest. FimH can adopt low/medium‐affinity state in absence and high‐affinity presence shear forces. Until recently, mostly been investigated, despite fact that therapeutic antagonist should bind predominantly low‐affinity state....
The organic anion transporting polypeptide (OATP) 2B1 is considered an emerging drug transporter that found expressed in pharmacokinetically relevant organs such as the liver, small intestine, and kidney. Despite its interaction with various substrate drugs, understanding of <i>in vivo</i> relevance still limited. In this study, we first validated atorvastatin rat OATP2B1 using transiently transfected HeLa cells. Moreover, characterized our <i>rSlco2b1</i>-knockout <i>SLCO2B1</i>-knockin...
A new class of N-acetyl-D-glucosamine (GlcNAc) mimics for E-selectin antagonists was designed and synthesized. The mimic consists a cyclohexane ring substituted with alkyl substituents adjacent to the linking position fucose moiety. Incorporation into led test compounds 8 2'-benzoylated analogues 21, which exhibit affinities in low micromolar range. By using saturation transfer difference (STD)-NMR it could be shown that increase affinity does not result from an additional hydrophobic...
Frequent antibiotic treatment of urinary tract infections has resulted in the emergence antimicrobial resistance, necessitating alternative options. One such approach centers around FimH antagonists that block bacterial adhesin FimH, which would otherwise mediate binding uropathogenic Escherichia coli to host urothelium trigger infection. Although lectin can adopt three distinct conformations, evaluation mainly been performed with a truncated construct locked one particular conformation. For...
Target-directed dynamic combinatorial chemistry (DCC) is an emerging technique for the efficient identification of inhibitors pharmacologically relevant targets. In this contribution, we present application a bacterial target, lectin FimH, crucial virulence factor uropathogenic E. coli being main cause urinary tract infections. A small library acylhydrazones was formed from aldehydes and hydrazides equilibrated at neutral pH in presence aniline as nucleophilic catalyst. The major success...
Antibiotic resistance is a major worldwide concern, and new drugs with mechanistically novel modes of action are urgently needed. Here, we report the structure-based drug design, synthesis, evaluation in vitro cellular systems sialic acid derivatives able to inhibit bacterial symporter SiaT. We designed synthesized 21 screened their affinity for SiaT by thermal shift assay elucidated inhibitory mechanism through binding thermodynamics, computational methods, kinetic studies. The most potent...
The d-GlcNAc moiety in sialyl Lewisx (sLex, 1) acts predominantly as a linker to position the d-Gal and l-Fuc moieties bioactive spatial orientation. hypothesis has been made that NHAc group of GlcNAc pushes fucose underneath galactose and, thus, contributes stabilization conformation core sLex (1). To test this hypothesis, mimetics consisting (R,R)-1,2-cyclohexanediols substituted with alkyl aryl substituents adjacent linking were synthesized. explore broad range extended spatially...
The lectin FimH is terminally expressed on type 1 pili of uropathogenic Escherichia coli (UPEC), which the main cause urinary tract infections (UTIs). enables bacterial adhesion to urothelial cells, initial step infection. Various mannose derivatives have been shown antagonize and are therefore considered be promising therapeutic agents for treatment UTIs. As part preclinical development process, when kinetic properties antagonists were examined by surface plasmon resonance, extremely low...