A New Experimental Model for Assessing Drug Efficacy against Trypanosoma cruzi Infection Based on Highly Sensitive In Vivo Imaging
The protozoan Trypanosoma cruzi is the causative agent of Chagas disease, one of the world’s major neglected infections. Although development of improved antiparasitic drugs is considered a priority, there have been no significant treatment advances in the past 40 years. Factors that have limited progress include an incomplete understanding of pathogenesis, tissue tropism, and disease progression. In addition, in vivo models, which allow parasite burdens to be tracked throughout the chronic stage of infection, have been lacking. To address these issues, we have developed a highly sensitive in vivo imaging system base...
Source: Journal of Biomolecular Screening - December 26, 2014 Category: Molecular Biology Authors: Lewis, M. D., Francisco, A. F., Taylor, M. C., Kelly, J. M. Tags: Review Articles Source Type: research
Chagas Disease Drug Discovery: Toward a New Era
American trypanosomiasis, or Chagas disease, is the result of infection by the Trypanosoma cruzi parasite. Endemic in Latin America where it is the major cause of death from cardiomyopathy, the impact of the disease is reaching global proportions through migrating populations. New drugs that are safe, efficacious, low cost, and adapted to the field are critically needed. Over the past five years, there has been increased interest in the disease and a surge in activities within various organizations. However, recent clinical trials with azoles, specifically posaconazole and the ravuconazole prodrug E1224, were disappointing...
Source: Journal of Biomolecular Screening - December 26, 2014 Category: Molecular Biology Authors: Chatelain, E. Tags: Review Articles Source Type: research
Diagnosis of Parasitic Infections: What's Going On?
This article examines the various diagnostic tools that are being used in clinical laboratories, optimized in reference laboratories, and employed in mass screening programs. (Source: Journal of Biomolecular Screening)
Source: Journal of Biomolecular Screening - December 26, 2014 Category: Molecular Biology Authors: Ricciardi, A., Ndao, M. Tags: Review Articles Source Type: research
Novel Therapeutic Approaches for Neglected Infectious Diseases
(Source: Journal of Biomolecular Screening)
Source: Journal of Biomolecular Screening - December 26, 2014 Category: Molecular Biology Authors: Martin-Plaza, J., Chatelain, E. Tags: Editorials Source Type: research
JBS: Advancing the Science of Drug Discovery for 20 Years!
(Source: Journal of Biomolecular Screening)
Source: Journal of Biomolecular Screening - December 26, 2014 Category: Molecular Biology Authors: Campbell, R. M. Tags: Editorials Source Type: research
Corrigendum
Kexiao Guo, Anang A. Shelat, R. Kiplin Guy, and Michael B. Kastan. Development of a Cell-Based, High-Throughput Screening Assay for ATM Kinase Inhibitors J. Biomol. Screen. 2014, 19(4)538-546. (Source: Journal of Biomolecular Screening)
Source: Journal of Biomolecular Screening - November 20, 2014 Category: Molecular Biology Tags: Corrigendum Source Type: research
Analytical and Preparative Instrumentation
(Source: Journal of Biomolecular Screening)
Source: Journal of Biomolecular Screening - November 20, 2014 Category: Molecular Biology Authors: McGee, J. Tags: Product Focus Source Type: research
Labware Additives Identified to Be Selective Monoamine Oxidase-B Inhibitors
We report herein the identification of biologically active substances released from a commonly used plastic microplate. The active contaminants were identified by gas chromatography–mass spectroscopy as dodecan-1-ol, dodecyl 3-(3-dodecoxy-3-oxopropyl)sulfanylpropanoate, and dodecanoic acid, and they were found to be selective monoamine oxidase-B inhibitors. (Source: Journal of Biomolecular Screening)
Source: Journal of Biomolecular Screening - November 20, 2014 Category: Molecular Biology Authors: Stewart, J., Drexler, D. M., Leet, J. E., McNaney, C. A., Herbst, J. J. Tags: Technical Notes Source Type: research
High Content Analysis of an In Vitro Model for Metabolic Toxicity: Results with the Model Toxicants 4-Aminophenol and Cyclophosphamide
In vitro models that accurately and rapidly assess hepatotoxicity and the effects of hepatic metabolism on nonliver cell types are needed by the U.S. Department of Defense and the pharmaceutical industry to screen compound libraries. Here, we report the first use of high content analysis on the Integrated Discrete Multiple Organ Co-Culture (IdMOC) system, a high-throughput method for such studies. We cultured 3T3-L1 cells in the presence and absence of primary human hepatocytes, and exposed the cultures to 4-aminophenol and cyclophosphamide, model toxicants that are respectively detoxified and activated by the liver. Follo...
Source: Journal of Biomolecular Screening - November 20, 2014 Category: Molecular Biology Authors: Cole, S. D., Madren-Whalley, J. S., Li, A. P., Dorsey, R., Salem, H. Tags: Technical Notes Source Type: research
High-Throughput Screening of Human Leukemia Xenografts to Identify Dexamethasone Sensitizers
In this study, we used high-throughput screening (HTS) to identify novel compounds that reverse dexamethasone resistance in a xenograft (ALL-19) derived from a chemoresistant pediatric ALL patient that is representative of the most common pediatric ALL subtype (B-cell precursor [BCP-ALL]). The compound 2-(4-chlorophenoxy)-2-methyl-N-(2-(piperidin-1-yl)phenyl)propanamide showed little cytotoxic activity alone (IC50 = 31 µM), but when combined with dexamethasone, it caused a marked decrease in cell viability. Fixed-ratio combination assays were performed against a broad panel of dexamethasone-resistant and -sensitive x...
Source: Journal of Biomolecular Screening - November 20, 2014 Category: Molecular Biology Authors: Toscan, C. E., Failes, T., Arndt, G. M., Lock, R. B. Tags: Original Research Source Type: research
Discovery of Novel DUSP16 Phosphatase Inhibitors through Virtual Screening with Homology Modeled Protein Structure
Recently, dual-specificity phosphatase 16 (DUSP16) emerged as a promising therapeutic target protein for the development of anti-atherosclerosis and anticancer medicines. The present study was undertaken to identify the novel inhibitors of DUSP16 based on the structure-based virtual screening. We have been able to find seven novel inhibitors of DUSP16 through the drug design protocol involving homology modeling of the target protein, docking simulations between DUSP16 and its putative inhibitors with the modified scoring function, and in vitro enzyme assay. These inhibitors revealed good potency, with IC50 values ranging f...
Source: Journal of Biomolecular Screening - November 20, 2014 Category: Molecular Biology Authors: Park, H., Park, S. Y., Nam, S.-W., Ryu, S. E. Tags: Original Research Source Type: research
Identification of a Putative Tdp1 Inhibitor (CD00509) by in Vitro and Cell-Based Assays
Mutations of DNA repair pathways contribute to tumorigenesis and provide a therapeutic target for synthetic lethal interactions in tumor cells. Given that tyrosyl-DNA phosphodiesterase 1 (Tdp1) repairs stalled topoisomerase-I DNA complexes, we hypothesized that inhibition of Tdp1 has synthetic lethal effects in some cancers. To test this, we screened tumor arrays for Tdp1 expression and observed that Tdp1 is expressed in many tumors, including more than 90% of human breast tumors. Subsequent chemical screening identified putative Tdp1 inhibitors. Treatment of control human mammary epithelial cells and the breast cancer cel...
Source: Journal of Biomolecular Screening - November 20, 2014 Category: Molecular Biology Authors: Dean, R. A., Fam, H. K., An, J., Choi, K., Shimizu, Y., Jones, S. J. M., Boerkoel, C. F., Interthal, H., Pfeifer, T. A. Tags: Original Research Source Type: research
Discovery of New Uncompetitive Inhibitors of Glucose-6-Phosphate Dehydrogenase
The enzyme glucose-6-phosphate dehydrogenase (G6PDH) catalyzes the first step of the oxidative branch of the pentose phosphate pathway, which provides cells with NADPH, an essential cofactor for many biosynthetic pathways and antioxidizing enzymes. In Trypanosoma cruzi, the G6PDH has being pursued as a relevant target for the development of new drugs against Chagas disease. At present, the best characterized inhibitors of T. cruzi G6PDH are steroidal halogenated compounds derivatives from the mammalian hormone precursor dehydroepiandrosterone, which indeed are also good inhibitors of the human homologue enzyme. The lack of...
Source: Journal of Biomolecular Screening - November 20, 2014 Category: Molecular Biology Authors: Mercaldi, G. F., Ranzani, A. T., Cordeiro, A. T. Tags: Original Research Source Type: research
Cell Lines Expressing Recombinant Transmembrane Domain-Activated Receptor Kinases as Tools for Drug Discovery
Many receptor tyrosine kinases (RTKs) represent bona fide drug targets in oncology. Effective compounds are available, but treatment invariably leads to resistance, often due to RTK mutations. The discovery of second-generation inhibitors requires cellular models of resistant RTKs.
An approach using artificial transmembrane domains (TMDs) to activate RTKs was explored for the rapid generation of simple, ligand-independent cellular RTK assays, including resistance mutants.
The RTKs epidermal growth factor receptor (EGFR), MET, and KIT were chosen in a proof-of-concept study. Their intracellular domains were inserted into a ...
Source: Journal of Biomolecular Screening - November 20, 2014 Category: Molecular Biology Authors: Weber, H., Muller, D., Muller, M., Ortiz, A., Birkle, M., Umber, S., Ketterer, C., Siedentopf, O., Feger, D., Totzke, F., Kubbutat, M., Schaechtele, C., Ballmer-Hofer, K., Ehlert, J. E., Graeser, R. Tags: Original Research Source Type: research
AlphaScreen HTS and Live-Cell Bioluminescence Resonance Energy Transfer (BRET) Assays for Identification of Tau-Fyn SH3 Interaction Inhibitors for Alzheimer Disease
Alzheimer disease (AD) is the most common neurodegenerative disease, and with Americans’ increasing longevity, it is becoming an epidemic. There are currently no effective treatments for this disorder. Abnormalities of Tau track more closely with cognitive decline than the most studied therapeutic target in AD, amyloid-β, but the optimal strategy for targeting Tau has not yet been identified. On the basis of considerable preclinical data from AD models, we hypothesize that interactions between Tau and the Src-family tyrosine kinase, Fyn, are pathogenic in AD. Genetically reducing either Tau or Fyn is protective ...
Source: Journal of Biomolecular Screening - November 20, 2014 Category: Molecular Biology Authors: Cochran, J. N., Diggs, P. V., Nebane, N. M., Rasmussen, L., White, E. L., Bostwick, R., Maddry, J. A., Suto, M. J., Roberson, E. D. Tags: Original Research Source Type: research
