Success Stories

Genetic and chemical modifiers of a CUG toxicity model in Drosophila


Garcia-Lopez A, Monferrer L, Garcia-Alcover I, Vicente-Crespo M, Alvarez-Abril MC, Artero RD
PLoS ONE - vol. 3 (2008)

Non-coding CUG repeat expansions interfere with the activity of human Muscleblind-like (MBNL) proteins contributing to myotonic dystrophy 1 (DM1). To understand this toxic RNA gain-of-function mechanism we developed a Drosophila model expressing 60 pure and 480 interrupted CUG repeats in the context of a non-translatable RNA. These flies reproduced aspects of the DM1 pathology, most […]

High-Throughput Screening Assay for the Identification of Compounds Regulating Self-Renewal and Differentiation in Human Embryonic Stem Cells

Cell Stem Cell

Desbordes SC, Placantonakis DG, Ciro A, Socci ND, Lee G, Djaballah H, Studer L
Cell Stem Cell - vol. 2 602-612 (2008)

High-throughput screening (HTS) of chemical libraries has become a critical tool in basic biology and drug discovery. However, its implementation and the adaptation of high-content assays to human embryonic stem cells (hESCs) have been hampered by multiple technical challenges. Here we present a strategy to adapt hESCs to HTS conditions, resulting in an assay suitable […]

Tiratricol neutralizes bacterial endotoxins and reduces lipopolysaccharide-induced TNF-α production in the cell

Chemical Biology and Drug Design

Cascales L, Mas-Moruno C, Tamborero S, Aceña JL, Sanz-Cervera JF, Fustero S, Cruz LJ, Mora P, Albericio F, Pérez-Payá E
Chemical Biology and Drug Design - vol. 72 320-328 (2008)

The screening of a commercially available library of compounds has proved a successful strategy for the identification of a lead compound in a drug discovery programme. Here, we analysed 880 off-patent drugs, which initially comprised the Prestwick Chemical library, as sources of bacterial endotoxin neutralizers. We identified 3,3′,5-triiodo-thyroacetic acid (tiratricol) as a non-antibacterial compound that […]

Known Bioactive Small Molecules Probe the Function of a Widely Conserved but Enigmatic Bacterial ATPase, YjeE

Chemistry and Biology

Mangat CS, Brown ED
Chemistry and Biology - vol. 15 1287-1295 (2008)

Escherichia coli YjeE is a broadly conserved bacterial ATPase of unknown function that has been widely characterized as essential. Here, the transcriptional regulation of the promoter of yjeE (P yjeE) was probed using a luciferase reporter and 172 antibiotics of diverse mechanisms. Norfloxacin and other fluorquinolones were found to be the most potent activator of […]

Identification of Tau Stem Loop RNA Stabilizers

Journal of Biomolecular Screening

Donahue CP, Ni J, Rozners E, Glicksman MA, Wolfe MS
Journal of Biomolecular Screening - vol. 12 789-799 (2007)

Alternative splicing of tau exon 10 produces tau isoforms with either 3 (3R) or 4 (4R) repeated microtubule-binding domains. Increased ratios of 4R to 3R tau expression, above the physiological 1:1, leads to neurofibrillary tangles and causes neurode-generative disease. An RNA stem loop structure plays a significant role in determining the ratio, with decreasing stability […]

Modeling promiscuity based on in vitro safety pharmacology profiling data


Azzaoui K, Hamon J, Faller B, Whitebread S, Jacoby E, Bender A, Jenkins JL, Urban L
ChemMedChem - vol. 2 874-880 (2007)

This study describes a method for mining and modeling binding data obtained from a large panel of targets (in vitro safety pharmacology) to distinguish differences between promiscuous and selective compounds. Two naïve Bayes models for promiscuity and selectivity were generated and validated on a test set as well as publicly available drug databases. The model […]

Analysis of pharmacology data and the prediction of adverse drug reactions and off-target effects from chemical structure


Bender A, Scheiber J, Glick M, Davies JW, Azzaoui K, Hamon J, Urban L, Whitebread S, Jenkins JL
ChemMedChem - vol. 2 861-873 (2007)

Preclinical Safety Pharmacology (PSP) attempts to anticipate adverse drug reactions (ADRs) during early phases of drug discovery by testing compounds in simple, in vitro binding assays (that is, preclinical profiling). The selection of PSP targets is based largely on circumstantial evidence of their contribution to known clinical ADRs, inferred from findings in clinical trials, animal […]

A comparison of the chemical properties of drugs and FEMA/FDA notified GRAS chemical compounds used in the food industry

Food and Chemical Toxicology

Sprous DG, Salemme FR
Food and Chemical Toxicology - vol. 45 1419-1427 (2007)

The range of molecular properties of generally recognized as safe (GRAS) compounds that are typically used in food and beverage products is compared to marketed drugs. It is observed that GRAS compounds differ from marketed drugs with respect to several molecular descriptors, including molecular weight, H-bond acceptor count, H-bond donor count, aromatic ring count, basic […]

Structure of Saccharomyces cerevisiae Chitinase 1 and Screening-Based Discovery of Potent Inhibitors

Chemistry and Biology

Hurtado-Guerrero R, van Aalten DMF
Chemistry and Biology - vol. 14 589-599 (2007)

Chitinases hydrolyse the ??(1,4)-glycosidic bonds of chitin, an essential fungal cell wall component. Genetic data on a subclass of fungal family 18 chitinases have suggested a role in??cell wall morphology. Specific inhibitors of these enzymes would be useful as tools to study their role in cell wall morphogenesis and could possess antifungal properties. Here, we […]

Differentiating Alzheimer disease-associated aggregates with small molecules

Neurobiology of Disease

Honson NS, Johnson RL, Huang W, Inglese J, Austin CP, Kuret J
Neurobiology of Disease - vol. 28 251-260 (2007)

Alzheimer disease is diagnosed postmortem by the density and spatial distribution of β-amyloid plaques and tau-bearing neurofibrillary tangles. The major protein component of each lesion adopts cross-β-sheet conformation capable of binding small molecules with submicromolar affinity. In many cases, however, Alzheimer pathology overlaps with Lewy body disease, characterized by the accumulation of a third cross-β-sheet […]