A5043448626- Protein Structure and Dynamics
- Carbohydrate Chemistry and Synthesis
- Glycosylation and Glycoproteins Research
- Chemical Synthesis and Analysis
- Immunotherapy and Immune Responses
- Bacteriophages and microbial interactions
- Enzyme Structure and Function
- Monoclonal and Polyclonal Antibodies Research
- Escherichia coli research studies
- Biochemical Acid Research Studies
- Synthesis and Biological Evaluation
- thermodynamics and calorimetric analyses
- vaccines and immunoinformatics approaches
- RNA Interference and Gene Delivery
- RNA and protein synthesis mechanisms
- Computational Drug Discovery Methods
- Viral Infections and Outbreaks Research
- Click Chemistry and Applications
- Protein purification and stability
- Biochemical effects in animals
- Protein Interaction Studies and Fluorescence Analysis
- ATP Synthase and ATPases Research
- Free Radicals and Antioxidants
- Galectins and Cancer Biology
- Immune cells in cancer
University of Basel
2019-2024
Heinrich Heine University Düsseldorf
2021-2024
Philipps University of Marburg
2016-2017
University of Würzburg
1968
A previously studied congeneric series of thermolysin inhibitors addressing the solvent-accessible S2′ pocket with different hydrophobic substituents showed modulations surface water layers coating protein-bound inhibitors. Increasing stabilization molecules resulted in an enthalpically more favorable binding signature, overall enhancing affinity. Based on this observation, we optimized by designing tailored P2′ to improve and further stabilize network. MD simulations were applied predict...
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...
Human chitinases and chitinase-like proteins (CLPs) provide the immune system with ability to recognize or process chitin originating from chitinous pathogens. In addition their role in host defense,...
In lead optimization, open, solvent-exposed protein pockets are often disregarded as prospective binding sites. Because of bulk-solvent proximity, researchers instead enticed to attach charged polar groups at inhibitor scaffolds improve solubility and pharmacokinetic properties. It is rarely considered that solvent effects from water reorganization in the first hydration shell protein-ligand complexes can have a significant impact on binding. We investigate thermodynamic fingerprint...
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....
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...
We investigated the hydration state of deep, well-accessible hydrophobic S1′ specificity pocket metalloprotease thermolysin with purposefully designed ligands using high-resolution crystallography and isothermal titration calorimetry. The is known to recognize selectively a very stringent set aliphatic side chains such as valine, leucine, isoleucine putative substrates. engineered weak-binding ligand covering active site protease without addressing pocket, thus transforming it into an...
Abstract The C‐type lectin receptor DC‐SIGN mediates interactions with envelope glycoproteins of many viruses such as SARS‐CoV‐2, ebola, and HIV contributes to virus internalization dissemination. In the context recent SARS‐CoV‐2 pandemic, involvement has been linked severe cases COVID‐19. Inhibition interaction between viral potential generate broad spectrum antiviral agents. Here, we demonstrate that mannose‐functionalized poly‐ l ‐lysine glycoconjugates efficiently inhibit attachment...
Due to the shallow and hydrophilic binding sites of carbohydrate-binding proteins, design glycomimetics is often complicated by high desolvation costs as well competition with solvent. Therefore, a careful optimization interaction vectors ligand properties required in glycomimetics. Here, we employ thermodynamics-guided optimize mannose-based targeting human C-type lectin receptor dendritic cell-specific intercellular adhesion molecule 3 grabbing nonintegrin (DC-SIGN), pathogenic host factor...
In biological systems, polar interactions are heavily burdened by high desolvation penalties resulting from strong solute-solvent interactions. As a consequence thereof, enthalpic contributions of hydrogen bonds to the free energy binding severely diminished. However, this effect is strongly attenuated for within solvent-shielded areas proteins. microcalorimetric experiments, we show that bacterial lectin FimH utilizes conformational adaptions effectively shield its site solvent. The...
Kinetic parameters of protein-ligand interactions are progressively acknowledged as valuable information for rational drug discovery. However, a targeted optimization binding kinetics is not easy to achieve, and further systematic studies necessary increase the understanding about molecular mechanisms involved. We determined association dissociation rate constants 17 inhibitors metalloprotease thermolysin by surface plasmon resonance spectroscopy correlated kinetic data with high-resolution...
Siglecs are members of the immunoglobulin gene family containing sialic acid binding N-terminal domains. Among them, Siglec-8 is expressed on various cell types immune system such as eosinophils, mast cells and weakly basophils. Cross-linking with monoclonal antibodies triggers apoptosis in eosinophils inhibits degranulation cells, making a promising target for treatment eosinophil- cell-associated diseases asthma. The tetrasaccharide 6'-sulfo-sialyl Lewisx has been identified specific...
Abstract With the rising popularity of fragment‐based approaches in drug development, more and attention has to be devoted detection false‐positive screening results. In particular, small size low affinity fragments drives techniques their limit. The pursuit a hit can cause significant loss time resources. Here, we present an instructive intriguing investigation into origin misleading assay results for fragment that emerged as most potent binder aspartic protease endothiapepsin (EP) across...
Abstract Burkholderia cenocepacia is an opportunistic Gram‐negative bacterium that causes infections in patients suffering from chronic granulomatous diseases and cystic fibrosis. It displays significant morbidity mortality due to extreme resistance almost all clinically useful antibiotics. The bacterial lectin BC2L‐C expressed B. interesting drug target involved adhesion subsequent deadly infection the host. We solved first high resolution crystal structure of apo form N‐terminal domain...
Siglec-7 regulates immune cell activity and is a promising target for immunomodulation. Here, we report the discovery of novel sialic acid derivatives binding to Siglec-7. Synthesis affinity measurements are complemented by high-quality models sialoside-Siglec-7 complexes based on molecular dynamics (MD) simulations microsecond time scale. We provide details predicted modes new ligands, e.g., that an extension carbon backbone leads different interaction pattern with receptor nearby water...
For modern biophysical methods such as isothermal titration calorimetry, high purity of the inhibitor interest is indispensable. Herein, we describe a procedure for synthesis and purification functionalized phosphonamidate peptides that able to generate inhibitors metalloprotease thermolysin use in experiments. The method utilizes an allyl ester/alloc protection strategy takes advantage fast effective solid-phase extraction (SPE) step. Applying this strategy, were synthesize series highly...
The selectin family consisting of E-, P- and L-selectin plays dominant roles in atherosclerosis, ischemia-reperfusion injury, inflammatory diseases, metastatic spreading some cancers. An early goal selectin-targeted drug discovery campaigns was to identify ligands binding all three selectins, so-called pan-selectin antagonists. physiological epitope, tetrasaccharide sialyl Lewis
Envelope glycoproteins of many viruses are heavily glycosylated. Among other functions, virus glycans can mediate interactions with host receptors and contribute to internalization dissemination. The C-type lectin receptor DC-SIGN, which is expressed by cells the innate immune system, act as an entry for pathogens, including pandemic such SARS-CoV-2, ebola, HIV. In context recent SARS-CoV-2 pandemic, this mechanism has been linked severe cases COVID-19. Inhibition interaction between DC-SIGN...