A5062444631- Signaling Pathways in Disease
- Endoplasmic Reticulum Stress and Disease
- Viral Infectious Diseases and Gene Expression in Insects
- Biochemical and Molecular Research
- Toxin Mechanisms and Immunotoxins
- Protein Structure and Dynamics
- Heat shock proteins research
- Adipose Tissue and Metabolism
- Enzyme Structure and Function
- Stress Responses and Cortisol
- Chemical Synthesis and Analysis
- Fluorine in Organic Chemistry
- Glycosylation and Glycoproteins Research
- Research on Leishmaniasis Studies
- Hormonal Regulation and Hypertension
- Receptor Mechanisms and Signaling
- Protein Degradation and Inhibitors
- Asymmetric Synthesis and Catalysis
- Pancreatic function and diabetes
Technical University of Darmstadt
2018-2024
Robert Bosch (Germany)
2021
Micron (United States)
2021
Micron Biomedical (United States)
2021
Harm Reduction Services
2021
Max Planck Institute of Psychiatry
2019
Universitätsklinikum Erlangen
2019
The FK506-binding protein 51 (FKBP51) emerged as a key player in several diseases like stress-related disorders, chronic pain, and obesity. Linear analogues of FK506 called SAFit were shown to be highly selective for FKBP51 over its closest homologue FKBP52, allowing the proof-of-concept studies animal models. Here, we designed synthesized first macrocyclic FKBP51-selective ligands stabilize active conformation. All macrocycles retained full affinity selectivity FKBP52 incorporation polar...
Methyl groups can have profound effects in drug discovery but the underlying mechanisms are diverse and incompletely understood. Here we report stereospecific effect of a single, solvent-exposed methyl group bicyclic [4.3.1] aza-amides, robustly leading to 2 10-fold increase binding affinity for FK506-binding proteins (FKBPs). This resulted most potent efficient FKBP ligands known date. By combination co-crystal structures, isothermal titration calorimetry (ITC), density-functional theory...
Antascomicin B is a natural product that similarly to the macrolides FK506 and Rapamycin binds FK506-binding protein 12 (FKBP12). act as molecular glues by inducing ternary complexes between FKBPs additional target proteins. Whether can induce unknown. Here we show tightly larger human FKBP homologs. The cocrystal structure of FKBP51 in complex with revealed large parts are solvent-exposed available engage Cellular studies demonstrated enhances interaction Akt. Our molecules glue-like...
Specific inhibition of G proteins holds a great pharmacological promise to, e.g., target oncogenic Gq/11 and can be achieved by the two natural products FR900359 (FR) YM-254890 (YM). Unfortunately, recent rational-design-based approaches to address other than Gq/11/14 subtypes were not successful mainly due conformational complexity these new modalities-like compounds. Here, we report water-derived NMR structure YM, which strongly differs from conformation Gq-bound YM as found in crystal...
Subtype selectivity represents a challenge in many drug discovery campaigns. A typical example is the FK506 binding protein 51 (FKBP51), which has emerged as an attractive target. The most advanced FKBP51 ligands of SAFit class are highly selective vs. FKBP52 but poorly discriminate against homologs and off-targets FKBP12 FKBP12.6. During macrocyclization pilot study, we observed that these macrocyclic analogs have unanticipated unprecedented preference for over Structural studies revealed...
Abstract There is still no widely effective pharmacotherapy for alcohol addiction available in the clinic. FK506‐binding protein 51 (FKBP51) a negative regulator of glucocorticoid receptor signaling pathway that regulates stress‐induced feedback circuit. Here we asked whether selective inhibitors FKBP51, exemplified by SAFit2, may serve as new pharmacological strategy to reduce consumption and conditioned effects mouse model. We report relatively short treatment with SAFit2 (20 mg/kg, ip)...
Alcohol addiction is a major psychiatric disorder with no widely effective pharmacotherapy available. The FK506-binding protein 51 (FKBP51) negative regulator of the glucocorticoid receptor signaling pathway where it controls stress-induced feedback circuit.
Abstract Subtyp‐Selektivität ist oft eine Herausforderung bei der Wirkstoffentwicklung. Ein Beispiel das FK506‐bindende Protein 51 (FKBP51) als Wirkstoffziel. Die am weitesten fortgeschrittenen FKBP51‐Liganden SAFit‐Klasse sind hochselektiv gegenüber FKBP52, differenzieren aber kaum den eng verwandten Proteinen FKBP12 und FKBP12.6. Eine Makrozyklisierungsstudie ergab, dass viele dieser makrozyklischen Analoga unerwartete, neuartige Präferenz für FKBP51 FKBP12.6 haben. Strukturellen Studien...
CycloparaphenylenesIn their Communication on page 13529, Michal Juríc ˇek et al. describe a neutral open-shell carbon nanoring and show that its reactivity is result of steric electronic effects the cycloparaphenylene framework.