A5059618965- Protein Degradation and Inhibitors
- Multiple Myeloma Research and Treatments
- Protein Structure and Dynamics
- Ubiquitin and proteasome pathways
- Various Chemistry Research Topics
- Tuberculosis Research and Epidemiology
- Biochemical and Molecular Research
- Monoclonal and Polyclonal Antibodies Research
- Innovative Teaching Methods
- HIV/AIDS drug development and treatment
- Lanthanide and Transition Metal Complexes
- Click Chemistry and Applications
- Yeasts and Rust Fungi Studies
- Computational Drug Discovery Methods
- Cancer-related gene regulation
- Plant Pathogens and Fungal Diseases
- Chemical Safety and Risk Management
- Signaling Pathways in Disease
- Enzyme Production and Characterization
- RNA Interference and Gene Delivery
- Receptor Mechanisms and Signaling
- Bacterial Genetics and Biotechnology
- Enzyme Structure and Function
- RNA and protein synthesis mechanisms
- Atomic and Subatomic Physics Research
St. Jude Children's Research Hospital
2019-2025
University of Minnesota
2015-2021
Resonance Research (United States)
2017
Minneapolis Institute of Arts
2016
University of Minnesota System
2016
Abstract Infections caused by fungal pathogens such as Candida and Cryptococcus are associated with high mortality rates, partly due to limitations in the current antifungal arsenal. This highlights need for drug targets novel mechanisms of action. The trehalose biosynthesis pathway is a promising target because essential virulence neoformans albicans also mediator stress responses, thermotolerance. To exploit its untapped potentials, we screened St. Jude 3-point pharmacophore library...
Chemical probes for epigenetic proteins are essential tools dissecting the molecular mechanisms gene regulation and therapeutic development. The bromodomain extra-terminal (BET) master transcriptional regulators. Despite promising targets, selective small molecule inhibitors a single remain an unmet goal due to their high sequence similarity. Here, we address this challenge via structure–activity relationship study using 1,4,5-trisubstituted imidazoles against BRD4 N-terminal (D1). Leading...
Proteins are involved in nearly every biological process, which makes them of interest to a range scientists. Previous work has shown that hand-held cameras can be used determine the concentration colored analytes solution, and this paper extends approach reactions involving color change order quantify protein (e.g., green blue). Herein, we describe successful use smartphone colorimetry using two common colorimetric biochemical methods, Bradford biuret assays. The ease experimental setup...
Abstract 19 F NMR spectroscopy of labeled proteins is a sensitive method for characterizing structure, conformational dynamics, higher‐order assembly, and ligand binding. Fluorination aromatic side chains has been suggested as labeling strategy small‐molecule discovery protein–protein interaction interfaces. Using model transcription factor binding domain the CREB protein (CBP)/p300, KIX, we report first full screen using protein‐observed spectroscopy. Screening 508 compounds validation by 1...
Oxygen homeostasis is important in the regulation of biological function. Disease progression can be monitored by measuring oxygen levels, thus producing information for design therapeutic treatments. Noninvasive measurements tissue oxygenation require development tools with minimal adverse effects and facile detection features interest. Fluorine magnetic resonance imaging (19F MRI) exploits intrinsic properties perfluorocarbon (PFC) liquids anatomical imaging, cell tracking, sensing....
Abstract PROTAC® (proteolysis-targeting chimera) molecules induce proximity between an E3 ligase and protein-of-interest (POI) to target the POI for ubiquitin-mediated degradation. Cooperative E3-PROTAC-POI complexes have potential achieve neo-substrate selectivity beyond that established by binding ligand alone. Here, we extend collection of ubiquitin ligases employable cooperative ternary complex formation include C-degron KLHDC2. Ligands were identified engage site in KLHDC2, subjected...
Chemical inhibition of epigenetic regulatory proteins BrdT and Brd4 is emerging as a promising therapeutic strategy in contraception, cancer, heart disease. We report an easily synthesized dihydropyridopyrimidine pan-BET inhibitor scaffold, which was uncovered via virtual screen followed by testing fluorescence anisotropy assay. Dihydropyridopyimidine 3 subjected to further characterization highly selective for the BET family bromodomains. Structure–activity relationship data ligand...
Abstract Testis-restricted melanoma antigen (MAGE) proteins are frequently hijacked in cancer and play a critical role tumorigenesis. MAGEs assemble with E3 ubiquitin ligases function as substrate adaptors that direct the ubiquitination of novel targets, including key tumor suppressors. However, how recognize their targets is unknown has impeded development MAGE-directed therapeutics. Here, we report structural basis for recognition by MAGE ligases. Biochemical analysis degron motif...
Increasing rates of drug-resistant Gram-negative (GN) infections, combined with a lack new GN-effective antibiotic classes, are driving the need for discovery agents. Bacterial metabolism represents an underutilized mechanism action in current antimicrobial therapies. Therefore, we sought to identify novel antimetabolites that disrupt key metabolic pathways and explore specific impacts these agents on bacterial metabolism. This study describes successful application this approach discover...
Isoxyl (ISO) and thiacetazone (TAC) are two antitubercular prodrugs that abolish mycolic acid biosynthesis kill Mycobacterium tuberculosis (Mtb) through the inhibition of essential type II fatty synthase (FAS-II) dehydratase HadAB. While mutations preventing ISO TAC either from being converted to their active form or covalently modifying target most frequent spontaneous associated with high-level resistance both drugs, molecular mechanisms underlying Mtb strains harboring missense in second,...
Protein-observed <sup>19</sup>F (PrOF) NMR is an emerging tool for ligand discovery.
The peptide binding protein DppA is an ABC transporter found in prokaryotes that has the potential to be used as drug delivery tool for hybrid antibiotic compounds. Understanding motifs and structures bind critical development of these bivalent This study focused on biophysical analysis MtDppA from M. tuberculosis. Analysis crystal structure revealed a SVA tripeptide was co-crystallized with protein. Further demonstrated shows very little affinity dipeptides but rather preferentially binds...
Protein-Observed Fluorine NMR (PrOF NMR) spectroscopy is an emerging technique for screening and characterizing small-molecule-protein interactions. The choice of which amino acid to label PrOF can be critical analysis. Here we report the first use a protein containing two different fluoroaromatic acids studies. Using KIX domain CBP/p300 as model system, examine ligand binding several small-molecule compounds elaborated from our previous fragment screen identify new site distinct those used...
Abstract 19 F NMR spectroscopy of labeled proteins is a sensitive method for characterizing structure, conformational dynamics, higher‐order assembly, and ligand binding. Fluorination aromatic side chains has been suggested as labeling strategy small‐molecule discovery protein–protein interaction interfaces. Using model transcription factor binding domain the CREB protein (CBP)/p300, KIX, we report first full screen using protein‐observed spectroscopy. Screening 508 compounds validation by 1...
Methyl lysine readers, specifically PHD fingers, are emerging epigenetic targets in human diseases. For example, several finger fusions implicated clinical cases of acute myeloid leukemia, highlighting the potential for inhibitors disease regulation. However, limited chemical matter targeting fingers exists. Here we report first fragment-based screen against BPTF to identify reported PHD-targeting small-molecule ligands. We used ligand-observed NMR a fragment library, followed by biophysical...
Curriculum-based undergraduate research experiences (CUREs) have been shown to increase student retention in STEM fields and are starting become more widely adopted chemistry curricula. Here we describe a 10-week CURE that is suitable for second-semester organic laboratory course. Students synthesize small molecules use protein-observed 19F (PrOF) NMR assess the molecule's binding affinity target protein. The project introduced students multistep synthesis, structure–activity relationship...
Methyl lysine readers, specifically PHD fingers, are emerging epigenetic targets in human diseases. For example, several finger fusions implicated clinical cases of acute myeloid leukemia, highlighting the potential for inhibitors disease regulation. However, limited chemical matter exists targeting fingers. Here we report first fragment-based screen against BPTF to identify reported PHD-targeting small molecule ligands. We used ligand-observed NMR a fragment library, followed by biophysical...