A5046572292- Chemical synthesis and alkaloids
- Synthesis and bioactivity of alkaloids
- Traditional and Medicinal Uses of Annonaceae
- Calcium signaling and nucleotide metabolism
- Synthetic Organic Chemistry Methods
- Asymmetric Synthesis and Catalysis
- Chemical Synthesis and Analysis
- Alkaloids: synthesis and pharmacology
- Cholesterol and Lipid Metabolism
- Synthesis and Biological Activity
- Cancer therapeutics and mechanisms
- Microbial Natural Products and Biosynthesis
- Synthesis and Biological Evaluation
- Marine Sponges and Natural Products
- Steroid Chemistry and Biochemistry
- Phytochemical compounds biological activities
- Advanced Synthetic Organic Chemistry
- Carbohydrate Chemistry and Synthesis
- Coordination Chemistry and Organometallics
- Analytical Chemistry and Chromatography
- Bioactive Compounds and Antitumor Agents
- Antifungal resistance and susceptibility
- Sirtuins and Resveratrol in Medicine
- Catalytic C–H Functionalization Methods
- Cancer Mechanisms and Therapy
Ludwig-Maximilians-Universität München
2016-2025
Center for Drug Evaluation and Research
2025
Institut für Urheber- und Medienrecht
2024
LMU Klinikum
2003-2021
Centre for Drug Research and Development
2017-2021
Center for Integrated Protein Science Munich
2018
University of Würzburg
2004-2005
Pharmalog (Germany)
1999
Technische Universität Braunschweig
1993-1998
Centre National de la Recherche Scientifique
1997
Growing up on a dairy farm protects children from allergy, hay fever, and asthma. A mechanism linking exposure to this endotoxin (bacterial lipopolysaccharide)-rich environment with protection has remained elusive. Here we show that chronic low-dose or dust mice developing house mite (HDM)-induced Endotoxin reduced epithelial cell cytokines activate dendritic cells (DCs), thus suppressing type 2 immunity HDMs. Loss of the ubiquitin-modifying enzyme A20 in lung epithelium abolished protective...
There is a growing recognition of the importance protein kinases in control alternative splicing. To define underlying regulatory mechanisms, highly selective inhibitors are needed. Here, we report discovery and characterization dichloroindolyl enaminonitrile KH-CB19, potent specific inhibitor CDC2-like kinase isoforms 1 4 (CLK1/CLK4). Cocrystal structures KH-CB19 with CLK1 CLK3 revealed non-ATP mimetic binding mode, conformational changes helix αC phosphate loop halogen bonding to hinge...
Ion selectivity is a defining feature of given ion channel and considered immutable. Here we show that the lysosomal TPC2, which hotly debated (Calcraft et al., 2009; Guo 2017; Jha 2014; Ruas 2015; Wang 2012), depends on activating ligand. A high-throughput screen identified two structurally distinct TPC2 agonists. One these evoked robust Ca2+-signals non-selective cation currents, other weaker Na+-selective currents. These properties were mirrored by Ca2+-mobilizing messenger, NAADP...
Azole drugs selectively target fungal sterol biosynthesis and are critical to our antifungal therapeutic arsenal. However, resistance this class of drugs, particularly in the major human mould pathogen Aspergillus fumigatus, is emerging reaching levels that have prompted some suggest there a realistic probability they will be lost for clinical use. The dominating pan-azole resistant isolates characterized by presence tandem repeat at least 34 bases (TR34) within promoter cyp51A, gene...
Benzodiazepines are psychoactive drugs with anxiolytic, sedative, skeletal muscle relaxant and amnestic properties. Recently triazolo-benzodiazepines have been also described as potent highly selective protein interaction inhibitors of bromodomain extra-terminal (BET) proteins, a family transcriptional co-regulators that play key role in cancer cell survival proliferation, but the requirements for high affinity this compound class bromodomains has not described. Here we provide insight into...
The phenothiazine system was identified as a favorable cap group for potent and selective histone deacetylase 6 (HDAC6) inhibitors. Here, we report the preparation systematic variation of phenothiazines their analogues containing benzhydroxamic acid moiety zinc-binding group. We evaluated ability to selectively inhibit HDAC6 by recombinant HDAC enzyme assay, determining protein acetylation levels in cells western blotting (tubulin vs acetylation), assessing effects on various cancer cell...
Cytokines and chemokines are produced secreted by a broad range of immune cells including macrophages. Remarkably, little is known about how these inflammatory mediators released from the various cells. Here, endolysosomal cation channel TRPML2 shown to play direct role in chemokine trafficking secretion murine To demonstrate acute involvement processes, first isoform-selective agonist was generated, ML2-SA1. ML2-SA1 not only found directly stimulate release CCL2 macrophages but also...
Lung emphysema and chronic bronchitis are the two most common causes of obstructive pulmonary disease. Excess macrophage elastase MMP-12, which is predominantly secreted from alveolar macrophages, known to mediate development lung injury emphysema. Here, we discovered endolysosomal cation channel mucolipin 3 (TRPML3) as a regulator MMP-12 reuptake broncho-alveolar fluid, driving in independently generated Trpml3-/- mouse models enlarged injury, further exacerbated after or tobacco smoke...
Abstract Chronic inflammatory diseases are a significant global burden and associated with dysregulated resolution of inflammation. Therefore, promoting the process is promising therapeutic approach. This study presents potent anti-inflammatory pro-resolving effects natural product-derived compound called C81. Administration C81 in window resolved inflammation murine imiquimod-induced psoriasis model, reduced microglial infiltration laser-induced choroidal neovascularisation model....
Haloperidol, a typical antipsychotic, has been shown to inhibit cholesterol biosynthesis by affecting Δ(7)-reductase, Δ(8,7)-isomerase, and Δ(14)-reductase activities, which results in the accumulation of different sterol intermediates. In present work, we investigated effects atypical or second-generation antipsychotics (SGA), such as clozapine, risperidone, ziprasidone, on intracellular lipid metabolism cell lines. All SGAs tested inhibited biosynthesis. Ziprasidone risperidone had same...
The provirus integration site for Moloney murine leukemia virus 1 (Pim-1) kinase is overexpressed in various tumors and has been linked to poor prognosis. Its role as proto-oncogene based on several Pim-1 target proteins involved pivotal cellular processes. Here, we explore the functional relevance of colon carcinoma.RNAi-based knockdown approaches, well a specific small molecule inhibitor, were used inhibit carcinoma cells. effects analyzed regarding proliferation, apoptosis, sensitization...
Background The chemotherapy of schistosomiasis currently depends on the use a single drug, praziquantel. In order to develop novel chemotherapeutic agents we are investigating enzymes involved in epigenetic modification chromatin. Sirtuins NAD+ dependent lysine deacetylases that wide variety cellular processes including histone deacetylation, and have been demonstrated be therapeutic targets various pathologies, cancer. Methodology, Principal Findings determine whether Schistosoma mansoni...
Abstract Chikungunya virus (CHIKV) is a globally spreading alphavirus against which there no commercially available vaccine or therapy. Here we use genome-wide siRNA screen to identify 156 proviral and 41 antiviral host factors affecting CHIKV replication. We analyse the cellular pathways in human genes are involved druggable targets. Twenty-one small-molecule inhibitors, some of FDA approved, targeting six pathways, have high activity vitro , with low toxicity. Three identified inhibitors...
Abstract Liver X receptor (LXR) agonism has theoretical potential for treating NAFLD/NASH, but synthetic agonists induce hyperlipidemia in preclinical models. Desmosterol, which is converted by Δ24‐dehydrocholesterol reductase (DHCR24) into cholesterol, a potent endogenous LXR agonist with anti‐inflammatory properties. We aimed to investigate the effects of DHCR24 inhibition on NAFLD/NASH development. Here, using APOE*3‐Leiden. CETP mice, well‐established translational model that develops...
Lysosomes and the endoplasmic reticulum (ER) are Ca2+ stores mobilized by second messengers NAADP IP3, respectively. Here, we establish signals between two sources as fundamental building blocks that couple local release to global changes in Ca2+. Cell-wide evoked activation of endogenous NAADP-sensitive channels on lysosomes comprise both components exhibit a major dependence ER despite their lysosomal origin. Knockout IP3 receptor delays these signals, whereas expression TPC2 accelerates...
Development of both potent and selective kinase inhibitors is a challenging task in modern drug discovery. The innate promiscuity largely results from ATP-mimetic binding to the hinge region. We present novel class substituted 7,8-dichloro-1-oxo-β-carbolines based on distinct structural features alkaloid bauerine C whose inhibitory activity does not rely canonical interactions. Intriguingly, cocrystal structures revealed an unexpected inverted mode presence halogen bonds with backbone...