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article

MRI in drug discovery

28 February 2012 | By Peter R. Allegrini, Novartis Institutes for BioMedical Research

MRI is widely used for clinical diagnosis as well as in research areas such as preclinical drug discovery, clinical development and also in therapy monitoring. MRI allows non-invasive acquisition of tomographic images of soft tissue with high resolution and contrast. Furthermore, its ability to assess organ function in a broad…

RedHill Biopharma has last patient visit in phase IIa study with RHB-104 for multiple sclerosis
RedHill Biopharma has last patient visit in phase IIa study with RHB-104 for multiple sclerosis
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Discovery and validation of biomarkers for multiple sclerosis

13 December 2011 | By Ole Pless and Sheraz Gul, European ScreeningPort GmbH

Multiple Sclerosis (MS) is an autoimmune disease leading to a chronic inflammation and degeneration of the central nervous system. It is one of the major neurological diseases with approximately 2.5 million suffering patients worldwide. Until now, the underlying mechanisms have not been fully elucidated, but the cause of the disease…

FIGURE 1 Schematic overview of a typical homology modelling procedure that is used to build threedimensional coordinates for a protein of unknown structure
FIGURE 1 Schematic overview of a typical homology modelling procedure that is used to build threedimensional coordinates for a protein of unknown structure
article

Status and challenges in structure-based drug discovery for G protein-coupled receptors

13 December 2011 | By Henri Xhaard, Head of Computational Drug Discovery Group, Centre for Drug Research, University of Helsinki

The central location of G protein-coupled receptors (GPCRs) at the interface between the interior and exterior of cells, as well as their key role in signalling events, make GPCRs a prominent class of pharmaceutical targets. To date, approximately 40 per cent of known drugs are thought to act on GPCRs…

FIGURE 1miRNAs can impact viral infection directly by interacting with viral genes or indirectly by regulating host genes that play a role in the infection. miRNAs are derived from transcripts that contain stem-loop structures which get recognised and processed by a series of enzymes to generate the short (~22 nt) duplex RNA. One strand of the duplex is preferentially incorporated into the RNA-induced silencing complex (RISC) and guides this complex to mRNAs or other viral elements that contain regions of complementarity to the miRNA
FIGURE 1miRNAs can impact viral infection directly by interacting with viral genes or indirectly by regulating host genes that play a role in the infection. miRNAs are derived from transcripts that contain stem-loop structures which get recognised and processed by a series of enzymes to generate the short (~22 nt) duplex RNA. One strand of the duplex is preferentially incorporated into the RNA-induced silencing complex (RISC) and guides this complex to mRNAs or other viral elements that contain regions of complementarity to the miRNA
article

microRNA manipulation as a host-targeted antiviral therapeutic strategy

13 December 2011 | By Nouf N. Laqtom, University of Edinburgh & King Abdulaziz University and Amy H. Buck, University of Edinburgh

microRNAs (miRNA) are a class of non-coding RNA that regulate the precise amounts of proteins expressed in a cell at a given time. These molecules were discovered in worms in 1993 and only known to exist in humans in the last decade. Despite the youth of the miRNA field, miRNA…

Jadenu
Jadenu
article

Expression profiling of circulating miRNAs as a novel non-invasive diagnostic tool

13 December 2011 | By Mirco Castoldi. Department of Pediatric Hematology, Oncology and Immunology University of Heidelberg

Cell-free nucleic acids circulating in human blood were first described in 19481. However, it was not until the work of Sorengon and colleagues was published in 19942 that the importance of circulating nucleic acid (cfNA) was recognised. Today, the detection of diverse type of cfNA3 in blood and other body…

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
article

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…