A5027036766- RNA and protein synthesis mechanisms
- Bacterial Genetics and Biotechnology
- DNA and Nucleic Acid Chemistry
- Advanced biosensing and bioanalysis techniques
- RNA Interference and Gene Delivery
- RNA modifications and cancer
- Enzyme Structure and Function
- Bacteriophages and microbial interactions
- Cancer therapeutics and mechanisms
- Antimicrobial Resistance in Staphylococcus
- Genomics and Phylogenetic Studies
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Protein Structure and Dynamics
- Synthesis and Biological Evaluation
- Glycosylation and Glycoproteins Research
- HIV/AIDS drug development and treatment
- thermodynamics and calorimetric analyses
- Nutrition, Genetics, and Disease
- Antibiotic Resistance in Bacteria
- Synthesis and Characterization of Heterocyclic Compounds
- Pharmacological Effects of Medicinal Plants
- Fullerene Chemistry and Applications
- Advanced MRI Techniques and Applications
- HIV Research and Treatment
- HER2/EGFR in Cancer Research
Bristol-Myers Squibb (United States)
2021-2024
Merck & Co., Inc., Rahway, NJ, USA (United States)
2015-2018
Rutgers, The State University of New Jersey
2001-2014
Joint Center for Structural Genomics
2014
University of Georgia
2013
Johnson University
2004-2012
Howard Hughes Medical Institute
2008-2010
Rutgers Cancer Institute of New Jersey
2003-2006
National Taiwan University
2004
Bacterial riboswitches are non-coding RNA structural elements that direct gene expression in numerous metabolic pathways. The key regulatory roles of riboswitches, and the urgent need for new classes antibiotics to treat multi-drug resistant bacteria, has led efforts develop small-molecules mimic natural riboswitch ligands inhibit pathways bacterial growth. Recently, we reported results a phenotypic screen targeting riboflavin biosynthesis pathway Gram-negative bacteria Escherichia coli...
Aminoglycoside antibiotics bind specifically to a conserved sequence of the 16S ribosomal RNA (rRNA) A site and interfere with protein synthesis. One model for mechanism underlying deleterious effects aminoglycosides on synthesis invokes drug-induced conformational change in rRNA that involves destacking two adenine residues (A1492 A1493 Escherichia coli) at site. We describe here fluorescence-based approach detecting characterizing this target rRNA. In approach, we insert fluorescent base...
Steady-state and time-resolved fluorescence techniques have been used to characterize the energetics dynamics associated with interaction of an E. coli 16 S rRNA A-site model oligonucleotide four aminoglycoside antibiotics that exhibit a broad range antibacterial activity. The results these characterizations suggest aminoglycoside-induced reduction in mobility adenine residue at position 1492 is more important determinant activity than drug affinity for A-site. This observation consistent...
DNA-binding response regulators (RRs) of the OmpR/PhoB subfamily alternate between inactive and active conformational states, with latter having enhanced affinity. Phosphorylation an aspartate residue in receiver domain, usually via phosphotransfer from a cognate histidine kinase, stabilizes conformation. Many available structures family proteins exhibit extensive interfaces N-terminal C-terminal domains. These invariably involve α4-β5-α5 face locus largest differences conformations surface...
Oxazole-containing macrocycles represent a promising class of anticancer agents that target G-quadruplex DNA. We report the results spectroscopic studies aimed at defining mode, energetics and specificity with which hexaoxazole-containing macrocycle (HXDV) binds to intramolecular quadruplex formed by human telomeric DNA model oligonucleotide d(T2AG3)4 in presence potassium ions. HXDV solely nucleic acid form, but not duplex or triplex form. stoichiometry two drug molecules per quadruplex,...
Abstract Several G-rich oligodeoxynucleotides (ODNs), which are capable of forming G-quadruplexes, have been shown to exhibit antiproliferative activity against tumor cell lines and antitumor in nude mice carrying prostate breast xenografts. However, the molecular basis for their remains unclear. In current study, we showed that a variety telomeric G-tail (TG-ODNs) exhibited many cells culture. Systematic mutational analysis TG-ODNs suggests depends on G-quadruplex conformation these...
The lack of absolute prokaryotic selectivity natural antibiotics is widespread and a significant clinical problem. use this disadvantage aminoglycoside for the possible treatment human genetic diseases extremely challenging. Here, we have used combination biochemical structural analysis to compare contrast molecular mechanisms action structure-activity relationships new synthetic aminoglycoside, NB33, structurally similar apramycin. data presented herein demonstrate general principles that...
ABSTRACT Oligomeric proteins are important targets for structure determination in solution. While most cases the fold of individual subunits can be determined experimentally, or predicted by homology‐based methods, protein–protein interfaces challenging to determine de novo using conventional NMR protocols. Here we focus on a member bet‐V1 superfamily, Aha1 from Colwellia psychrerythraea . This family displays broad range crystallographic none which reconciled with and SAXS data collected...
We describe the design, synthesis, and structure-activity relationship (SAR) of heterobifunctional RET ligand-directed degraders (LDDs) derived from three different second-generation inhibitors. These LDDs are composed a target binding motif (TBM) that binds to protein, linker, cereblon (CBM) as E3 ligase recognition unit. This led identification series pyrazolopyridine-based LDDs, exemplified by compound
Spectroscopic and calorimetric techniques were employed to characterize contrast the binding of aminoglycoside paromomycin three octamer nucleic acid duplexes identical sequence but different strand composition (a DNA·RNA hybrid duplex corresponding DNA·DNA RNA·RNA duplexes). In addition, impact on both RNase H- A-mediated cleavage RNA in was also determined. Our results reveal following significant features: (i) Paromomycin enhances thermal stabilities similar extents, with this enhancement...
Small molecules that bind to allosteric sites on target proteins alter protein function are highly sought in drug discovery. High-throughput screening (HTS) assays needed facilitate the direct discovery of allosterically active compounds. We have developed technology for high-throughput time-resolved fluorescence lifetime detection resonance energy transfer (FRET), which enables modulators by monitoring changes structure. tested this approach at industrial scale adapting an FRET sensor...
2-Deoxystreptamine (2-DOS) aminoglycosides exert their antibiotic actions by binding to the A site of 16S rRNA and interfering with bacterial protein synthesis. However, molecular forces that govern antitranslational activities are poorly understood. Here, we describe studies aimed at elucidating these forces. In this connection, compare bactericidal, antitranslational, properties 4,5-disubstituted 2-DOS aminoglycoside neomycin (Neo) a conformationally restricted analog Neo (CR-Neo) in which...
Coagulation Factor XII (FXII) plays a critical role in thrombosis. What is unclear the level of enzyme occupancy FXIIa that needed for efficacy and impact inhibition on cerebral embolism. A selective activated FXII (FXIIa) inhibitor, recombinant human albumin-tagged mutant Infestin-4 (rHA-Mut-inf), was generated to address these questions. rHA-Mut-inf displayed potency comparable original wild-type HA-Infestin-4 (human constant = 0.07 0.12 nM, respectively), with markedly improved...