A5071859243- Mosquito-borne diseases and control
- Malaria Research and Control
- Peptidase Inhibition and Analysis
- Computational Drug Discovery Methods
- Chemical Synthesis and Analysis
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- HIV Research and Treatment
- Neuropeptides and Animal Physiology
- Synthesis and biological activity
- Click Chemistry and Applications
- Research on Leishmaniasis Studies
- Viral Infections and Vectors
- Monoclonal and Polyclonal Antibodies Research
- Protein Structure and Dynamics
- Hepatitis C virus research
- Pharmacogenetics and Drug Metabolism
- Prostate Cancer Treatment and Research
- Mass Spectrometry Techniques and Applications
- Microbial Natural Products and Biosynthesis
- RNA and protein synthesis mechanisms
- Bacterial Identification and Susceptibility Testing
- Hormonal Regulation and Hypertension
- HIV/AIDS drug development and treatment
- Signaling Pathways in Disease
Heidelberg University
2015-2025
Agilent Technologies (United States)
2014-2023
Heidelberg (Poland)
2020
German Center for Infection Research
2019
Santa Clara University
2018
Springer Nature (Germany)
2014
Saarland University
2001-2009
Kiel University
2008
Max Planck Institute of Biochemistry
2006
Max Planck Society
2006
Ion mobility-mass spectrometry measurements which describe the gas-phase scaling of molecular size and mass are both fundamental pragmatic utility. Fundamentally, such expand our understanding intrinsic intramolecular folding forces in absence solvent. Practically, reproducible transport properties, as collision cross-section (CCS), analytically useful metrics for identification characterization purposes. Here, we report 594 CCS values obtained nitrogen drift gas on an electrostatic tube ion...
The ongoing Zika virus (ZIKV) outbreak is linked to severe neurological disorders. ZIKV relies on its NS2B/NS3 protease for polyprotein processing; hence, this enzyme an attractive drug target. 2.7 angstrom; crystal structure of in complex with a peptidomimetic boronic acid inhibitor reveals cyclic diester between the and glycerol. P2 4-aminomethylphenylalanine moiety forms salt-bridge nonconserved Asp(83) NS2B; ion-pairing residue substrate likely accounts enzyme's high catalytic...
Rhodanines and related five-membered heterocycles with multiple heteroatoms have recently gained a reputation of being unselective compounds that appear as "frequent hitters" in screening campaigns therefore little value drug discovery. However, this judgment appears to be based mostly on anecdotal evidence. Having identified various rhodanines campaigns, we decided perform systematic study their promiscuity. An amount 163 rhodanines, hydantoins, thiohydantoins, thiazolidinediones were...
Bupropion is applied in depression and smoking cessation. Genetic polymorphisms cytochrome P450 2B6 (CYP2B6) may cause variability bupropion pharmacokinetics since hydroxylation known to be mediated by CYP2B6. a probe drug for CYP2B6 activity humans. were studied after single oral dose of 150 mg 121 healthy male volunteers. The amino acid R22C, Q172H, S259R, K262R R487C analysed polymerase chain reaction restriction fragment length polymorphism plasma concentrations measured high-performance...
With as few seven residues, acyclic α/β-peptides, which consist of alternating units (L)-alanine and cis-β-aminocyclopropanecarboxylic acids (cis-β-ACCs, see structure), form stable 313-helix turns in solution. The configuration the cis-β-ACCs was found to be crucial for helical structure this new class foldamers.
Covalent ligand-target interactions offer significant pharmacological advantages. However, off-target reactivity of the reactive groups, which usually have electrophilic properties, must be minimized, and selectivity irreversible inhibitors is a crucial requirement. We therefore performed systematic study to determine several groups that can used as building blocks for covalently binding ligands. Six with modulated electrophilicity were combined 11 nonreactive moieties, resulting in small...
A thousand-fold affinity gain is achieved by introduction of a C-terminal boronic acid moiety into dipeptidic inhibitors the Zika, West Nile, and dengue virus proteases. The resulting compounds have Ki values in two-digit nanomolar range, are not cytotoxic, inhibit replication. Structure-activity relationships high resolution X-ray cocrystal structure with Nile protease provide basis for design optimized covalent-reversible aimed at emerging flaviviral pathogens.
The protease of dengue virus is a promising target for antiviral drug discovery. We here report new generation peptide–hybrid inhibitors that incorporate N-substituted 5-arylidenethiazolidinone heterocycles (rhodanines and thiazolidinediones) as N-terminal capping groups the peptide moiety. compounds were extensively characterized with respect to inhibition various proteases, mechanisms, membrane permeability, activity, cytotoxicity in cell culture. A sulfur/oxygen exchange position 2...
The dengue virus (DENV) and West Nile Virus (WNV) NS2B-NS3 proteases are attractive targets for the development of dual-acting therapeutics against these arboviral pathogens. We present synthesis extensive biological evaluation inhibitors that contain benzyl ethers 4-hydroxyphenylglycine as non-natural peptidic building blocks synthesized via a copper-complex intermediate. A three-step optimization strategy, beginning with fragment growth C-terminal to benzyloxy ether, followed by C-...
Dengue virus is an increasingly global pathogen. One of the promising targets for antiviral drug discovery against dengue and related flaviviruses such as West Nile viral serine protease NS2B-NS3. We here report synthesis in vitro characterization potent peptidic inhibitors that incorporate phenylalanine phenylglycine derivatives arginine-mimicking groups with modulated basicity. The most compounds were (4-amidino)-L-phenylalanine-containing inhibitors, which reached nanomolar affinities...
The Zika virus presents a major public health concern due to severe fetal neurological disorders associated with infections in pregnant women. In addition vaccine development, the discovery of selective antiviral drugs is essential combat future epidemic outbreaks. NS2B-NS3 protease, which performs replication-critical cleavages viral polyprotein, promising drug target. We report first macrocyclic peptide-based inhibitors discovered de novo through vitro display screening genetically...
Structure-guided drug design relies on detailed structural knowledge of protein-ligand complexes, but crystallization cocomplexes is not always possible. Here we present a sensitive nuclear magnetic resonance (NMR) approach to determine the binding mode tightly lead compounds in complex with difficult target proteins. In contrast established NMR methods, it does depend rapid exchange between bound and free ligand or stable isotope labeling, relying instead tert-butyl group as chemical label....
We report the discovery of thiabendazole as a potent inhibitor (Ki = 0.4 μM) Escherichia coli methionine aminopeptidase (ecMetAP) and synthesis pharmacological evaluation congeners with activity in upper nanomolar range. Elucidation X-ray structure ecMetAP complex an unrelated that was independently described by another group showed both compounds bind to additional CoII ion at entrance active site. This unexpected finding explains inactivity under vivo conditions. It also allows us discuss...
Dengue virus protease is a promising target for the development of antiviral drugs. We describe here two-step rational optimization that led to discovery potent inhibitor 35 with nanomolar binding affinity at dengue serotype 2 (IC50 = 0.6 μM, Ki 0.4 μM). First, large number natural and non-natural amino acids were screened C-terminal position previously reported, canonical peptide sequence (Cap-Arg-Lys-Nle-NH2). Compared reference compound 1 (Bz-Arg-Lys-Nle-NH2, IC50 13.3 μM), 4-fold higher...
Boronic acids are an increasingly important compound class for many applications, including C–C bond formation reactions, medicinal chemistry, and diagnostics. The deprotection of boronic ester intermediates is frequently a problematic inefficient step in acid syntheses. We describe approach that highly facilitates this transformation by leveraging the volatility methylboronic its diol esters. method performed under mild conditions, provides high yields, eliminates cumbersome purification steps.