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PubMed Journal Database | SLAS discovery : advancing life sciences R & D RSS

16:43 EDT 17th October 2019 | BioPortfolio

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Showing PubMed Articles 1–25 of 92 from SLAS discovery : advancing life sciences R & D

A Mass Spectrometric Assay of METTL3/METTL14 Methyltransferase Activity.

A variety of covalent modifications of RNA have been identified and demonstrated to affect RNA processing, stability, and translation. Methylation of adenosine at the N6 position (mA) in messenger RNA (mRNA) is currently the most well-studied RNA modification and is catalyzed by the RNA methyltransferase complex METTL3/METTL14. Once generated, mA can modulate mRNA splicing, export, localization, degradation, and translation. Although potent and selective inhibitors exist for several members of the Type I -a...

Automating Complex, Multistep Processes on a Single Robotic Platform to Generate Reproducible Phosphoproteomic Data.

Mass spectrometry-based phosphoproteomics holds promise for advancing drug treatment and disease diagnosis; however, its clinical translation has thus far been limited. This is in part due to an unstandardized and segmented sample preparation process that involves cell lysis, protein digestion, peptide desalting, and phosphopeptide enrichment. Automating this entire sample preparation process will be key in facilitating standardization and clinical translation of phosphoproteomics. While peptide desalting a...

Screening of Chemical Libraries Using a Yeast Model of Retinal Disease.

Retinitis pigmentosa (RP) is a degenerative retinal disease, often caused by mutations in the G-protein-coupled receptor rhodopsin. The majority of pathogenic rhodopsin mutations cause rhodopsin to misfold, including P23H, disrupting its crucial ability to respond to light. Previous screens to discover pharmacological chaperones of rhodopsin have primarily been based on rescuing rhodopsin trafficking and localization to the plasma membrane. Here, we present methods utilizing a yeast-based assay to screen fo...

Membrane Proteins: New Approaches to Probes, Technologies, and Drug Design.

Development of a High-Throughput Fluorescence Polarization Assay to Detect Inhibitors of the FAK-Paxillin Interaction.

Focal adhesion kinase (FAK) is a promising cancer drug target due to its massive overexpression in multiple solid tumors and its critical role in the integration of signals that control proliferation, invasion, apoptosis, and metastasis. Previous FAK drug discovery and high-throughput screening have exclusively focused on the identification of inhibitors that target the kinase domain of FAK. Because FAK is both a kinase and scaffolding protein, the development of novel screening assays that detect inhibitor...

Rebuttal to Response to the Article "Enzyme-Inhibitor Interactions and a Simple, Rapid Method for Determining Inhibition Modality".

Response to the Article "Enzyme-Inhibitor Interactions and a Simple, Rapid Method for Determining Inhibition Modality".

Cytotoxic Profiling of Annotated and Diverse Chemical Libraries Using Quantitative High-Throughput Screening.

Cell-based phenotypic screening is a commonly used approach to discover biological pathways, novel drug targets, chemical probes, and high-quality hit-to-lead molecules. Many hits identified from high-throughput screening campaigns are ruled out through a series of follow-up potency, selectivity/specificity, and cytotoxicity assays. Prioritization of molecules with little or no cytotoxicity for downstream evaluation can influence the future direction of projects, so cytotoxicity profiling of screening libra...

Lysyl-tRNA Synthetase from : Characterization and Identification of Inhibitory Compounds.

is an opportunistic pathogen that causes nosocomial infections and has highly developed systems for acquiring resistance against numerous antibiotics. The gene (S) encoding lysyl-tRNA synthetase (LysRS) was cloned and overexpressed, and the resulting protein was purified to 98% homogeneity. LysRS was kinetically evaluated, and the values for the interaction with lysine, adenosine triphosphate (ATP), and tRNA were determined to be 45.5, 627, and 3.3 µM, respectively. The values were calculated to be 13, ...

The National Cancer Institute's Plated Compound Sets Can Be a Valuable Resource for Academic Researchers.

Academic researchers looking for material to screen may benefit from plated compound collections provided at no cost except shipping by the U.S. National Cancer Institute (NCI). Four plated sets are available, two of which comprise diverse synthetic compounds. These collections, of ~900 and ~1500 compounds, are a convenient size to screen without automated equipment, and a great deal of data about the compounds is available that increases their usefulness. Despite these positive attributes, the collections ...

Live Cell Membranome cDNA Screen: A Novel Homogenous Live Cell Binding Assay to Study Membrane Protein-Ligand Interaction.

Interactions between transmembrane receptors and their ligands play important roles in normal biological processes and pathological conditions. However, the binding partners for many transmembrane-like proteins remain elusive. To identify potential ligands of these orphan receptors, we developed a screening platform using a homogenous nonwash binding assay in live cells. A collection of ~1900 cDNA clones, encoding full-length membrane proteins, was assembled. As a proof of concept, cDNA clones were individu...

Stabilization of Human Multidrug Resistance Protein 4 (MRP4/ABCC4) Using Novel Solubilization Agents.

Membrane proteins (MPs) are important drug discovery targets for a wide range of diseases. However, elucidating the structure and function of native MP is notoriously challenging as their original structure has to be maintained once removed from the lipid bilayer. Conventionally, detergents have been used to solubilize MP with varying degrees of success concerning MP stability. To try to address this, new, more stabilizing agents have been developed, such as calixarene-based detergents and styrene-maleic ac...

Functional Expression of Multidrug Resistance Protein 4 MRP4/ABCC4.

To study the function and structure of membrane proteins, high quantities of pure and stable protein are needed. One of the first hurdles in accomplishing this is expression of the membrane protein at high levels and in a functional state. Membrane proteins are naturally expressed at low levels, so finding a suitable host for overexpression is imperative. Multidrug resistance protein 4 (MRP4) or ATP-binding cassette subfamily C member 4 (ABCC4) is a multi-transmembrane protein that is able to transport a ra...

Targeting the Mitochondrial Potassium Channel Kv1.3 to Kill Cancer Cells: Drugs, Strategies, and New Perspectives.

Cancer is the consequence of aberrations in cell growth or cell death. In this scenario, mitochondria and ion channels play a critical role in regard to cell proliferation, malignant angiogenesis, migration, and metastasis. In this review, we focus on Kv1.3 and specifically on mitoKv1.3, which showed an aberrant expression in cancer cells compared with healthy tissues and which is involved in the apoptotic pathway. In recent years, mitoKv1.3 has become an oncological target since its pharmacological modulat...

Novel Cell-Based Assay for Identification of LRRK2 Inhibitors Using Its Aberrant Regulation of a Pluripotency Gene.

Mutations in the gene encoding leucine-rich repeat kinase 2 (), such as the G2019S mutation, are the most common cause of familial Parkinson's disease (PD). The G2019S mutation impairs neurite outgrowth. We hypothesized that those effects could be related to an altered expression of pluripotency genes, which may provide a readout for a screening assay based on function. Here, we show that the G2019S mutation mediates a sustained aberrant upregulation of the transcription factors and that in are downregu...

SLC6A14, a Pivotal Actor on Cancer Stage: When Function Meets Structure.

SLC6A14 (ATB) is a sodium- and chloride-dependent neutral and dibasic amino acid transporter that regulates the distribution of amino acids across cell membranes. The transporter is overexpressed in many human cancers characterized by an increased demand for amino acids; as such, it was recently acknowledged as a novel target for cancer therapy. The knowledge on the molecular mechanism of SLC6A14 transport is still limited, but some elegant studies on related transporters report the involvement of the 12 tr...

A Cell-Based Luminescence Reporter Plasmid Assay for High-Throughput Screening to Identify Novel FDA-Approved Drug Inhibitors of HPV-16 Infection.

Like cervical cancer, anal cancer is caused by human papillomavirus (HPV). HPV is the most common sexually transmitted agent and is found in the anal canal of almost all HIV-positive men who have sex with men (MSM). Rates of HPV anal cancer are disproportionately higher in this population. Although the nanovalent HPV vaccine is efficacious in protecting against oncogenic HPV types, a substantial proportion of MSM remains unvaccinated and anal HPV infection continues to be an important public health burden. ...

Identification of the Tetraspanin CD9 as an Interaction Partner of Organic Cation Transporters 1 and 2.

Organic cation transporters (OCTs) are membrane proteins with relevant physiological (because they accept neurotransmitters as substrate) and pharmacological (because of their interaction with drugs) roles. The human OCTs hOCT1 (/hOCT1) and hOCT2 (/hOCT2) are highly expressed in hepatic (hOCT1) and in renal and neuronal tissue (hOCT2), suggesting a possible role in modulating neurotransmitter activity in the liver, kidney, and brain, and their clearance from the blood. Even though there are several data dem...

A Whole-Cell Screen for Adjunctive and Direct Antimicrobials Active against Carbapenem-Resistant Enterobacteriaceae.

Carbapenem-resistant Enterobacteriaceae (CRE) are an emerging antimicrobial resistance threat for which few if any therapeutic options remain. Identification of new agents that either inhibit CRE or restore activity of existing antimicrobials is highly desirable. Therefore, a high-throughput screen of 182,427 commercially available compounds was used to identify small molecules which either enhanced activity of meropenem against a carbapenem-resistant ST258 screening strain and/or directly inhibited its gr...

Identification of a New Inhibitor That Stabilizes Interleukin-2-Inducible T-Cell Kinase in Its Inactive Conformation.

Interleukin-2-inducible T-cell kinase (ITK) plays an important role in T-cell signaling and is considered a promising drug target. As the ATP binding sites of protein kinases are highly conserved, the design of selective kinase inhibitors remains a challenge. Targeting inactive kinase conformations can address the issue of kinase inhibitor selectivity. It is important for selectivity considerations to identify compounds that stabilize inactive conformations from the primary screen hits. Here we screened a l...

Expanding the Biological Application of Fluorescent Benzothiadiazole Derivatives: A Phenotypic Screening Strategy for Anthelmintic Drug Discovery Using Caenorhabditis elegans.

The current methodologies used to identify promising new anthelmintic compounds rely on subjective microscopic examination of worm motility or involve genetic modified organisms. We describe a new methodology to detect worm viability that takes advantage of the differential incorporation of the fluorescent molecular marker propidium iodide and the 2,1,3-benzothiadiazole core, which has been widely applied in light technology. The new assay developed could be validated using the "Pathogen Box" library. By us...

Selection of Functional Intracellular Nanobodies.

Camelid-derived nanobodies are versatile tools for research, diagnostics, and therapeutics. Certain nanobodies can function as intrabodies and bind antigens within the eukaryotic cytosol. This capability is valuable for the development of intracellular probes and targeted gene therapies. Consequently, many attempts have been made to produce nanobodies that are intracellularly stable and resistant to aggregation. Pursuit of these intrabodies generally focuses on library design or nanobody selection method. R...

Application of Ion Chromatography Coupled with Mass Spectrometry for Human Serum and Urine Metabolomics.

Biomarkers that indicate the presence or severity of organ damage caused by diseases and toxicities are useful diagnostic tools. Metabolomics platforms using chromatography coupled with mass spectrometry (MS) have been widely used for biomarker screening. In this study, we aimed to establish a novel metabolomics platform using ion chromatography coupled with MS (IC-MS) for human biofluids. We found that ethylenediaminetetraacetic acid (EDTA) plasma is not suitable for IC-MS metabolomics platforms because of...

High-Throughput Surface Liquid Absorption and Secretion Assays to Identify F508del CFTR Correctors Using Patient Primary Airway Epithelial Cultures.

High-throughput screening for drug discovery is increasingly utilizing cellular systems of high physiological relevance, such as patient primary cells and organoid cultures. We used 3D-cultured cystic fibrosis patient bronchial epithelial cells to screen for new small-molecule correctors of the disease-causing F508del mutation in CFTR. Impaired mucociliary clearance due to insufficient airway hydration is a hallmark of cystic fibrosis and we used a simple measure of surface liquid levels to quantify F508del...

Chemical Derivatization Enables MALDI-TOF-Based High-Throughput Screening for Microbial Trimethylamine (TMA)-Lyase Inhibitors.

Microbial-dependent trimethylamine (TMA) generation from dietary precursors such as choline was recently linked to cardiovascular diseases (CVDs) as well as chronic kidney disease (CKD). Inhibition of TMA-generating enzymes in gut bacteria would be an innovative approach to treat these diseases. The potential to accurately quantify secreted TMA levels highlights the capacity of mass spectrometry (MS) for tracking microbial TMA-lyase activity. However, high-throughput screening (HTS) by conventional MS instr...


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