A5064886958- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Crystallography and molecular interactions
- Enzyme Structure and Function
- Peptidase Inhibition and Analysis
- Ubiquitin and proteasome pathways
- RNA and protein synthesis mechanisms
- Click Chemistry and Applications
- Protein Degradation and Inhibitors
- Protein Structure and Dynamics
- Porphyrin and Phthalocyanine Chemistry
- Neuropeptides and Animal Physiology
- Monoclonal and Polyclonal Antibodies Research
- Enzyme Catalysis and Immobilization
- Cancer-related gene regulation
- Mass Spectrometry Techniques and Applications
- Photoreceptor and optogenetics research
- RNA modifications and cancer
- Vibrio bacteria research studies
- Porphyrin Metabolism and Disorders
- Polyamine Metabolism and Applications
- PI3K/AKT/mTOR signaling in cancer
- Viral Infections and Vectors
- Pharmacological Receptor Mechanisms and Effects
- Photosynthetic Processes and Mechanisms
Janssen (United States)
2019-2024
Johnson & Johnson (United States)
2024
Pfizer (United States)
2012-2016
Global Science & Technology (United States)
2013
Andover Eye Associates
2013
Massachusetts General Hospital
2011
University of Minnesota
2007-2011
Louisiana State University
2009
Centrum Badań Molekularnych i Makromolekularnych Polskiej Akademii Nauk
2007
Abstract Dengue fever represents a significant medical and socio-economic burden in (sub)tropical regions, yet antivirals for treatment or prophylaxis are lacking. JNJ-A07 was described as highly active against the different genotypes within each serotype of disease-causing dengue virus (DENV). Based on clustering resistance mutations it has been assumed to target DENV non-structural protein 4B (NS4B). Using photoaffinity labeling compound with high structural similarity JNJ-A07, here we...
To facilitate the delivery of nucleotide-based therapeutics to cells and tissues, a variety pronucleotide approaches have been developed. Our laboratory others demonstrated that nucleoside phosphoramidates can be activated intracellularly corresponding 5'-monophosphate nucleotide histidine triad binding proteins (Hints) are potentially responsible for their bioactivation. Hints conserved ubiquitous enzymes hydrolyze phosphoramidate bonds between an amine leaving group. On basis ability...
Normal growth and development depends upon high fidelity regulation of cap-dependent translation initiation, a process that is usurped redirected in cancer to mediate acquisition malignant properties. The epithelial-to-mesenchymal transition (EMT) key translationally regulated step the epithelial cancers pathological tissue fibrosis. To date, no compounds targeting EMT have been developed. Here we report synthesis novel class histidine triad nucleotide binding protein (HINT)-dependent...
Enzyme engineering for improved catalysis has wide implications. We describe a novel chemical modification of Candida antarctica lipase B that allows modulation the enzyme conformation to promote catalysis. Computational modeling was used identify dynamical regions impact catalytic mechanism. Surface loop located distal active site but showing coupling reaction were connected by bridge between Lys136 and Pro192, containing derivative azobenzene. The conformational achieved using two sources...
β-Strands are a fundamental component of protein structure, and these extended peptide regions serve as binding epitopes for numerous protein-protein complexes. However, synthetic mimics that capture the conformation inhibit selected interactions rare. Here we describe covalent noncovalent β-hairpin an strand region mediating Tcf4/β-catenin interaction. Our efforts afford rationally designed lead underexplored β-catenin, which has been subject ligand discovery campaigns.
The serine hydrolase monoacylglycerol lipase (MAGL) is the rate-limiting enzyme responsible for degradation of endocannabinoid 2-arachidonoylglycerol (2-AG) into arachidonic acid and glycerol. Inhibition 2-AG leads to elevation 2-AG, most abundant endogenous agonist cannabinoid receptors (CBs) CB1 CB2. Activation these has demonstrated beneficial effects on mood, appetite, pain, inflammation. Therefore, MAGL inhibitors have potential produce therapeutic in a vast array complex human...
Abstract Proteolysis Targeting Chimeras (PROTACs) are an emerging therapeutic modality and chemical biology tools for Targeted Protein Degradation (TPD). PROTACs contain a ligand targeting the protein of interest, recruiting E3 ligase linker connecting these two ligands. There over 600 ligases known so far, but only handful have been exploited TPD applications. A key reason this is scarcity ligands binding various paucity structural data available, which complicates design across family. In...
Hint1 is a homodimeric protein and member of the ubiquitous HIT superfamily. catalyzes hydrolysis purine phosphoramidates lysyl-adenylate generated by lysyl-tRNA synthetase (LysRS). To determine importance homodimerization on biological catalytic activity Hint1, dimer interface human (hHint1) was destabilized replacement Val(97) hHint1 with Asp, Glu, or Arg. The mutants were shown to exist as monomers in solution combination size exclusion chromatograph, static light scattering, chemically...
The application of click chemistry to the visualization chemical probes in in-cell biology experiments is reviewed and influence this research has had on target validation molecular mode action studies also highlighted.
Histidine triad nucleotide binding proteins (Hints) are highly conserved members of the histidine (HIT) protein superfamily. Hints comprise most ancient branch this superfamily and can be found in Archaea, Bacteria, Eukaryota. Prokaryotic genomes, including a wide diversity both gram-negative gram-positive bacteria, typically have one Hint gene encoded by hinT (ycfF E. coli). Despite their ubiquity, foundational reason for wide-spread conservation across all kingdoms life remains mystery. In...
We present a new family of dipyrrins, whose spectral properties are tunable over the visible/near infrared range by way annealing pyrrolic residues with external aromatic fragments. Complexes π-extended many metal ions were found to be highly fluorescent, and their fluorescence is modulated depending on mode coordination. Structural spectroscopic data consolidated basis Kasha's exciton coupling theory, suggesting rational pathways practically useful fluorogenic dipyrrin-based ligands....
Summary Most human proteins lack chemical probes, and several large-scale generalizable small-molecule binding assays have been introduced to address this problem. How compounds discovered in such “binding-first” affect protein function, nonetheless, often remains unclear. Here, we describe a “function-first” proteomic strategy that uses size exclusion chromatography (SEC) assess the global impact of electrophilic on complexes cells. Integrating SEC data with cysteine-directed activity-based...
Photoaffinity labeling (PAL) methodologies have proven to be instrumental for the unbiased deconvolution of protein-ligand binding events in physiologically relevant systems. However, like other chemical proteomic workflows, they are limited many ways by time-intensive sample manipulations and data acquisition techniques. Here, we describe an approach address this challenge through innovation a carboxylate bead-based protein cleanup procedure remove excess small-molecule contaminants couple...
Human plasma-derived α1-antitrypsin (AAT) delivered by intravenous infusion is used as augmentation therapy in patients with emphysema who have a genetic mutation resulting deficiency of AAT. Inhalation an alternative route administration that can potentially increase the efficacy and convenience treatment. This study was conducted to determine whether delivery lungs, initially via intratracheal (IT) administration, would deliver efficacious levels recombinant AAT (rAAT) site action lungs...