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FIGURE 1 siRNA design principles. (A) Highly effective standard siRNAs have a guide strand (in green) with a less thermodynamically stable 5’ than 3’ end (indicated with dashed lines) and position-specific nucleotide preferences (indicated above guide strand). P and OH indicate 5’ phosphate groups and 3’ hydroxyl ends, respectively; blue region indicate seed region. (B) Bi-functional siRNAs targeting a single or (C) two different transcripts. (D) A dual-targeting siRNA where one strand (light green) targets EGFR and the other strand (dark green) targets CCND1
FIGURE 1 siRNA design principles. (A) Highly effective standard siRNAs have a guide strand (in green) with a less thermodynamically stable 5’ than 3’ end (indicated with dashed lines) and position-specific nucleotide preferences (indicated above guide strand). P and OH indicate 5’ phosphate groups and 3’ hydroxyl ends, respectively; blue region indicate seed region. (B) Bi-functional siRNAs targeting a single or (C) two different transcripts. (D) A dual-targeting siRNA where one strand (light green) targets EGFR and the other strand (dark green) targets CCND1
article

Unconventional RNA interference – recent approaches to robust RNAi

19 October 2011 | By Marie Lundbæk, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology and Pål Sætrom, Department of Cancer Research and Molecular Medicine & Department of Computer and Information Science, Norwegian University of Science and Technology

RNA interference (RNAi) is now a standard tool in molecular biology. Short interfering RNAs (siRNAs) for knocking down your favourite human gene are only a couple of mouse-clicks away at your favourite reagent supplier’s website. Moreover, in contrast to initial attempts at siRNA design, these siRNAs usually give potent target…

FIGURE 1 Nested HOX gene expression along the anterior to posterior axis. The expression domains of members of the HOXB group are illustrated, superimposed on the spinal cord of an early vertebrate. The combined expression of HOX genes in defined spatial positions is a key determinate of cell and tissue identity
FIGURE 1 Nested HOX gene expression along the anterior to posterior axis. The expression domains of members of the HOXB group are illustrated, superimposed on the spinal cord of an early vertebrate. The combined expression of HOX genes in defined spatial positions is a key determinate of cell and tissue identity
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HOX genes: HOX transcription factors as biomarkers in cancer

19 October 2011 | By Richard Morgan, Postgraduate Medical School, Faculty of Health and Medical Sciences, University of Surrey

The HOX genes are a family of closely related transcription factors that help to define the identity of cells and tissues during embryonic development and which are also frequently deregulated in cancer, where they have been shown to promote cell survival and proliferation. The high level of cancer-associated HOX expression…

FIGURE 1 Structures of active and inactive conformations of the β2 adrenoceptor Structures of the β2 adrenoceptor (light grey) in an inactive conformation with the antagonist carazolol bound (left33), and in an active conformation in complex with Gs (dark grey) and the agonist BI-167107 bound (right41). In both cases, the ligand is represented by black spheres to show the location of the orthosteric binding site within the membrane-spanning region of the protein. T4 lysozyme (black) is inserted in the third intracellular loop between helices 5 and 6 in the inactive structure (bottom left), and fused in the extracellular N-terminus for the active structure (top right), to remove flexibility and to provide polar surfaces for crystallisation. The nanobody (black, bottom right) served to stabilise the open conformation of Gs and also provided crystallisation contacts
FIGURE 1 Structures of active and inactive conformations of the β2 adrenoceptor Structures of the β2 adrenoceptor (light grey) in an inactive conformation with the antagonist carazolol bound (left33), and in an active conformation in complex with Gs (dark grey) and the agonist BI-167107 bound (right41). In both cases, the ligand is represented by black spheres to show the location of the orthosteric binding site within the membrane-spanning region of the protein. T4 lysozyme (black) is inserted in the third intracellular loop between helices 5 and 6 in the inactive structure (bottom left), and fused in the extracellular N-terminus for the active structure (top right), to remove flexibility and to provide polar surfaces for crystallisation. The nanobody (black, bottom right) served to stabilise the open conformation of Gs and also provided crystallisation contacts
article

Lead discovery for targeting G protein-coupled receptors

19 October 2011 | By Sandra Siehler and Sandra W. Cowan-Jacob, Novartis Institutes for BioMedical Research

G protein-coupled receptors (GPCRs) control a plethora of key physiological functions in every cell of an organism. GPCRs are therefore involved in many diseases, since altered ligand or receptor levels and genetic or epigenetic modifications can lead to GPCR dysfunction and hence a pathophysiological phenotype. About one third of currently…

Figure 1 Schematic illustration of a particle stabilised by a steric stabiliser. Note that it has been reported that both the degree of adsorption and the density / thickness of the steric barrier are essential factors to mitigate freezing and drying stresses
Figure 1 Schematic illustration of a particle stabilised by a steric stabiliser. Note that it has been reported that both the degree of adsorption and the density / thickness of the steric barrier are essential factors to mitigate freezing and drying stresses
article

Stabilisation of nanoparticles during freeze drying: The difference to proteins

31 August 2011 | By Jakob Beirowski and Henning Gieseler, University of Erlangen-Nuremberg, Division of Pharmaceutics, Freeze Drying Focus Group

The underlying concept for the stabilisation of proteins during freeze drying is the formation of a glassy matrix in which the macromolecules remain isolated and immobilised. The concept relies on the so-called ‘vitrification hypothesis’ which assumes that the formation of an amorphous phase by lyoprotectants is mandatory to interact with…

Flow Cytometry
Flow Cytometry
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Implementation of flow cytometric biomarker assays in clinical development

20 June 2011 | By Dianna Y. Wu & Russell Weiner, Clinical Biomarkers and Diagnostics, Merck & Co

Biomarker research has become one of the integral aspects in drug discovery and development. It is broadly utilised to confirm drug mechanism of action (MOA), explore PK/PD correlation, support dose selection and predict response to treatment. Therefore, biomarker data provide valuable information to guide clinical decisions, support drug filings with…

Sheraz Gul
Sheraz Gul
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Reducing attrition in drug discovery: The role of biomarkers

20 June 2011 | By Sheraz Gul, Vice President & Head of Biology, European ScreeningPort GmbH

The development of most diseases is often attributed to the dysfunction of the activities of key proteins involved in biological processes and their modulation by a therapeutic agent is considered to offer the potential to alleviate the disease state.

AstraZeneca announces collaborations to use CRISPR technology for genome editing across its drug discovery platform
AstraZeneca announces collaborations to use CRISPR technology for genome editing across its drug discovery platform
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Using translational pharmacology biomarkers to drive earlier decision making

19 April 2011 | By Magnus Ivarsson, Head of Physiological Biomarkers, Pfizer and Mark Fidock, Head of Quantitative Biomarkers, Research Enabling Group, Pfizer

The current high rate of attrition during drug development is unsustainable. An increasing amount of the cost of developing a new drug is made up of the investment in molecules that fail at some point during the process and the later that failure occurs, the more costly it will be.…

article

DiscoveRx Interview

19 April 2011 | By Sailaja Kuchibhatla, Senior Vice President Business Development DiscoveRx Corporation

“The goal of DiscoveRx has always been centred on creating technologies that enable the highest levels of innovation and development to enrich drug discovery,” Sailaja Kuchibhatla, Senior Vice President Business Development, asserts. Founded in 2000, DiscoveRx solved an unmet need within the GPCR industry by commercialising a functional, naturally coupled…

Figure 1 Examples of chemical structures of antibodies for targeted pulmonary inhalation aerosol
Figure 1 Examples of chemical structures of antibodies for targeted pulmonary inhalation aerosol
article

Pulmonary inhalation aerosols for targeted antibiotics drug delivery

16 February 2011 | By Chun-Woong Park & Heidi M. Mansour, University of Kentucky, College of Pharmacy and Don Hayes Jr, University of Kentucky, College of Medicine

Targeted pulmonary drug delivery of antibiotics by inhalation aerosols can play significant roles in the treatment of cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD) and in other pulmonary diseases where chronic airway infections exist. Direct administration to the lung as targeted pulmonary inhalation aerosol delivery is uniquely able to…

Figure 1 Schematic illustration of arrayed or pooled RNAi screens in cells. Left panel. Pooled-viral vectors encoding libraries of shRNAs targeting multiple genes can be used to transduce a target cell population in a single tissue culture dish. After selection for the desired phenotype, cells are analysed for the identification of genes whose inhibition by RNAi knockdown cause the specific phenotype as described in Table 1. The relative abundance of each shRNA or a random 60-mer barcode expressed from the same vector as the specific shRNA can be identified and quantified by labelling the PCR product with fluorescent dyes (e.g., Cy5 or Cy3). The PCR products are then hybridised to custom designed cDNA microarrays containing barcode or shRNA complementary oligonucleotides. The relative abundance of barcodes obtained from the cells that were exposed to selective pressure are compared to that detected in control cells that have been exposed to the same shRNA library, but not to the selective pressure (for example, drug treatment or genetic mutations). Right panel. Arrayed RNAi screen libraries consist of individual siRNA or shRNA reagents that target different genes and that are placed in each well of a multi-well plate. RNAi reagent libraries can comprise synthetic siRNAs, plasmid-or virally-encoded shRNAs. Various assay readouts are used to determine the effect of RNAi on the phenotype as described in Table 1. Adapted10.
Figure 1 Schematic illustration of arrayed or pooled RNAi screens in cells. Left panel. Pooled-viral vectors encoding libraries of shRNAs targeting multiple genes can be used to transduce a target cell population in a single tissue culture dish. After selection for the desired phenotype, cells are analysed for the identification of genes whose inhibition by RNAi knockdown cause the specific phenotype as described in Table 1. The relative abundance of each shRNA or a random 60-mer barcode expressed from the same vector as the specific shRNA can be identified and quantified by labelling the PCR product with fluorescent dyes (e.g., Cy5 or Cy3). The PCR products are then hybridised to custom designed cDNA microarrays containing barcode or shRNA complementary oligonucleotides. The relative abundance of barcodes obtained from the cells that were exposed to selective pressure are compared to that detected in control cells that have been exposed to the same shRNA library, but not to the selective pressure (for example, drug treatment or genetic mutations). Right panel. Arrayed RNAi screen libraries consist of individual siRNA or shRNA reagents that target different genes and that are placed in each well of a multi-well plate. RNAi reagent libraries can comprise synthetic siRNAs, plasmid-or virally-encoded shRNAs. Various assay readouts are used to determine the effect of RNAi on the phenotype as described in Table 1. Adapted10.
article

RNAi screens for the identification and validation of novel targets: Current status and challenges

16 December 2010 | By Attila A. Seyhan, Translational Immunology, Inflammation and Immunology, Pfizer Pharmaceuticals

Recent advances in RNA interference (RNAi) technology and availability of RNAi libraries in various formats and genome coverage have impacted the direction and speed of drug target discovery and validation efforts. After the introduction of RNAi inducing reaagent libraries in various formats, systematic functional genome screens have been performed to…

Figure 1 A: Control B: Docetaxel treated Induction of apoptosis with Docetaxel compared to untreated. The lower right quadrant represents cells in early apoptosis and cells in the upper right quadrant are cells in late apoptosis due to PI entering the cells through leaky membranes. C: Control D: Docetaxel treated Cell cycle of control cells and Docetaxel treated cells. The first peak shows cells in G0/G1 and the second peak is cells in G2/M. The breast cancer cell line, MDA MB231, was treated with 10nM docetaxel or DMSO control for 72 hours. Cells were harvested, the nuclei isolated and stained with PI. Samples were run on the LSR II flow cytometer and analyed in FCS Express software. Docetaxel arrests the cells in G2/M
Figure 1 A: Control B: Docetaxel treated Induction of apoptosis with Docetaxel compared to untreated. The lower right quadrant represents cells in early apoptosis and cells in the upper right quadrant are cells in late apoptosis due to PI entering the cells through leaky membranes. C: Control D: Docetaxel treated Cell cycle of control cells and Docetaxel treated cells. The first peak shows cells in G0/G1 and the second peak is cells in G2/M. The breast cancer cell line, MDA MB231, was treated with 10nM docetaxel or DMSO control for 72 hours. Cells were harvested, the nuclei isolated and stained with PI. Samples were run on the LSR II flow cytometer and analyed in FCS Express software. Docetaxel arrests the cells in G2/M
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Application of flow cytometry in drug discovery

16 December 2010 | By Dana Buckman, Senior Scientist, Biomarkers – Translational Research, Pfizer

Flow cytometry can be used to advance our understanding of diseases in multiple ways. Drug effects and dosages can be ascertained in vitro, along with patient selection based on mutations and antigen profiles. Within the Diagnostic Biomarkers group of Translational Research at Pfizer, we are utilising flow cytometry in conjunction…