A5027635963- Cell death mechanisms and regulation
- RNA Interference and Gene Delivery
- Botulinum Toxin and Related Neurological Disorders
- Receptor Mechanisms and Signaling
- DNA and Nucleic Acid Chemistry
- Biochemical and Structural Characterization
- Synthesis and Characterization of Heterocyclic Compounds
- interferon and immune responses
- Chemical Synthesis and Analysis
- Synthetic Organic Chemistry Methods
- Cellular transport and secretion
- Organometallic Complex Synthesis and Catalysis
- Neuroendocrine regulation and behavior
- Advanced biosensing and bioanalysis techniques
- Advanced Fluorescence Microscopy Techniques
- RNA and protein synthesis mechanisms
- Synthesis of heterocyclic compounds
- Cancer Mechanisms and Therapy
- Pharmacological Effects and Assays
- Biopolymer Synthesis and Applications
- Retinoids in leukemia and cellular processes
- PARP inhibition in cancer therapy
- Diabetes Treatment and Management
- Chronic Obstructive Pulmonary Disease (COPD) Research
- vaccines and immunoinformatics approaches
Boehringer Ingelheim (Germany)
2015-2023
AbbVie (Germany)
2018
Abbott (Germany)
2005-2011
Leibniz University Hannover
1997-2010
Abbott Fund
2010
Abbott (United States)
2000-2007
University of Wisconsin–Madison
2000-2006
General Atomics (United States)
2004
Neurocrine Biosciences (United States)
2004
Discovery Laboratories (United States)
2003
Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated tumor growth, pathogenesis, resistance to chemo- or radiotherapy. On the basis NMR structure a SMAC peptide complexed with BIR3 domain X-linked IAP (XIAP), novel series XIAP antagonists was discovered. The most potent compounds this bind baculovirus repeat 3 (BIR3) single-digit nanomolar affinity promote cell death several human cancer lines. In MDA-MB-231 breast mouse xenograft model, these...
Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a common mechanism through which cancer cells gain survival advantage become resistant to conventional chemotherapy. Inhibition these prosurvival is an attractive strategy for therapy. We recently described discovery selective antagonist that potentiates antitumor activity chemotherapy radiation. Here we describe use structure-guided design exploit deep hydrophobic binding pocket on surface develop first dual, subnanomolar...
Development of a rationally designed potentiator cancer chemotherapy, via inhibition Bcl-XL function, is described. Lead compounds generated by NMR screening and directed parallel synthesis displayed sub-μM binding but were strongly deactivated in the presence serum. The dominant component serum deactivation was identified as domain III human albumin (HSA); solution structures inhibitors bound to both HSA indicated two potential optimization sites for separation affinities. Modifications at...
A method is described for the NMR-based screening discovery of aminoglycoside mimetics that bind to Escherichia coli A-site RNA. Although aminoglycosides are clinically useful, they exhibit high nephrotoxicity and ototoxicity, their overuse has led development resistance important microbial pathogens. To identify a new series could potentially overcome problems associated with toxicities observed aminoglycosides, we have prepared large quantities E. 16 S RNA conducted an our compound library...
Activating the stimulator of interferon genes (STING) pathway with STING agonists is an attractive immune oncology concept to treat patients tumors that are refractory single-agent anti-PD-1 therapy. For best clinical translatability and broad application cancer patients, potent cellular activation all variants desired. Novel cyclic dinucleotide (CDN)-based selective were designed synthesized comprising noncanonical nucleobase, ribose, phosphorothioate moieties. This strategy led discovery...
Abstract: Botulinum neurotoxin (BoNT) metalloproteases and related proteases are the most selective known. X‐ray crystal structures suggest that active sites of native enzymes exist in catalytically incompetent forms must be activated by substrate binding. In order to characterize postulated substrate‐induced conformational changes for enzyme activation, we synthesized a series transition‐state analog inhibitors which dipeptide cleavage site is replaced tetrahedral intermediate analogs...
ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTADDITION / CORRECTIONThis article has been corrected. View the notice.Structural Basis for BABIM Inhibition of Botulinum Neurotoxin Type B ProteaseMichael A. Hanson, Thorsten K. Oost, Chanokporn Sukonpan, Daniel H. Rich, and Raymond C. StevensView Author Information Department Chemistry Molecular Biology The Scripps Research Institute La Jolla, California 92037 School Pharmacy University Wisconsin-Madison, 425 N. Charter Street Madison,...
Abstract Botulinum toxin (BoNT) metalloproteases and related proteases are the most selective known. X‐ray crystal structures suggest that native enzymes exist in catalytically incompetent forms must be activated by substrate binding. In order to characterize postulated substrate‐induced conformational changes, we synthesized a series of transition state analog inhibitors (TSI) which dipeptide cleavage site has been replaced tetrahedral intermediate analogs within minimal peptide sequence....
Abstract Various bis(guanidinium) compounds have been synthesized and their abilities to cleave the RNA model compound HPNPP tested in acetonitrile water. Depending on spacer length, substitution of guanidinium groups, presence an internal base, different rate constants for transesterification are observed these two media. The steroid derived 12 was identified as a superior system.
ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionORIGINAL ARTICLEThis notice is a correctionStructural Basis for BABIM Inhibition of Botulinum Neurotoxin Type B Protease [J. Am. Chem. Soc.2000, 122, 11268−11269]., Thorsten K. Oost, Chanokporn Sukonpan, Daniel H. Rich, and Raymond C. StevensCite this: J. Soc. 2002, 124, 34, 10248Publication Date (Web):August 3, 2002Publication History Published online3 August 2002Published inissue 1...
Abstract Introduction: Stimulator of interferon genes (STING) is activated by cyclic dinucleotides that are generated GMP-AMP synthase in the presence cytosolic DNA, resulting a type 1 response and secretion pro-inflammatory cytokines. BI-STING mimics natural ligand STING hijacks signaling pathway to trigger potent anti-tumor immune response. Here we report pre-clinical characterization human cells lines vitro, ex vivo systems mouse models. Methods: Activity specificity were tested vitro...
ADVERTISEMENT RETURN TO ISSUEPREVLetterNEXTSequencing Hydroxyethylamine-Containing Peptides via Edman DegradationMatthias BrewerMatthias BrewerDepartment of Chemistry and School Pharmacy, University Wisconsin-Madison, Madison, Wisconsin 53706, The Protein Nucleic Acid Shared Facility Department Biochemistry, Medical College Wisconsin, Milwaukee, 53226 Email: [email protected].More by Matthias Brewer, Thorsten OostThorsten OostDepartment Oost, Chanokporn SukonpanChanokporn SukonpanDepartment...
<b>Background:</b> Excess activity of neutrophil elastase (NE) in the lung COPD patients results degradation extracellular matrix (ECM) proteins and an increased activation other proteases, leading to destruction alveolar septa and, ultimately, emphysema development. Direct inhibition NE is expected reduce parenchyma destruction, formation progression with COPD. <b>Aim:</b> We investigated vitro vivo profile novel inhibitor BI 1323495. <b>Methods:</b> Inhibition human related proteases...