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Novartis Institutes for BioMedical Research - Articles and news items
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 sense renders this technique to a versatile tool to answer specific scientific questions such as drug actions in disease models. Imaging of patho-physiological mechanisms and molecular processes are primarily in the focus of MRI in drug research. Finally, MRI is translational and has thus the potential to bridge the gap between preclinical research on one hand and clinical development or therapy monitoring on the other.
The magnetic moment of some atomic nuclei and with this, nuclear magnetic resonance (NMR), the basis of Magnetic Resonance Imaging (MRI), was predicted in the 1920s by Wolfgang Pauli and successfully demonstrated by Felix Bloch and Edward Purcell in 1946. With the detection of the chemical shift, the technique developed to a powerful analytical method for elucidation of chemical structures. Only decades later, in 1973, Paul Lauterbur published the first image based on NMR signal1. The breakthrough of MRI came with the intro – duction of the gradient based imaging techniques shortly thereafter as developed by Sir Peter Mansfield2. All these persons were later honoured for their contributions to NMR and MRI with the Nobel Prize.
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 marketed drugs target GPCRs. The human genome contains 720-800 predicted GPCRs, and about half of them respond to olfactory/sensory signals, whereas the others are known or predicted to be activated by endogenous ligands and many of these represent potential drug targets. Seventy seven per cent of these non-sensory GPCRs belong to the class A (rhodopsin-like) family, whereas 14 per cent represent class B (secretin-like) GPCRs, less than one per cent belong to the class C (metabotropic receptor-like) or the atypical frizzled-/smoothened receptor class, and the remaining 25 per cent are orphan receptors…
Since its introduction in the field of biomedical imaging over 10 years ago, matrixassisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI) has played an ever increasing role in drug discovery and development and is now utilised in laboratories of many leading pharmaceutical companies and collaborating academic institutions. The need for mass spectrometry imaging in drug discovery is founded on the shortcomings of current technologies. Traditional methods of spatially mapping the distribution of compounds in tissue involved a combination approach of autoradiography (WBA) with metabolite information obtained from LC/MS analysis of tissue homogenate. Autoradiography methods only monitor the radiolabel and therefore are not able to distinguish the parent drug from its metabolites. The addition of LC/MS allows for conclusive determination of metabolites. However, this only produces spatial information at the whole organ level and not the spatial detail that can be routinely achieved using MSI…
In the past decade, the pharmaceutical industry has exploited the naturally occurring cellular RNAi pathway to enhance drug discovery research. The RNAi pathway, triggered by dsRNA, selectively, although not always specifically, degrades mRNA leading to substantial decreases in post-transcriptional gene expression1. Researchers have capitalised on this intrinsic pathway by synthesising RNAi reagents to modify the expression of any desired gene. RNAi libraries consisting of synthetic siRNAs or plasmid based shRNAs are amendable to largescale genome-wide screening campaigns to search for new therapeutic targets. Such loss of function screens can reveal novel targets and synthetic lethal interactions for cancer therapy2,3. These screens have also been used to identify novel host factors for diseases such as Hepatitis C4-7 and HIV8-14. Selective gene silencing can deconvolute molecular pathways implicated in disease onset and progression15.
Drug Targets, Issue 4 2010 / 19 August 2010 / Gül Erdemli & Dmitri Mikhailov, Center for Proteomic Chemistry, Novartis Institutes for BioMedical Sciences and Albert M Kim, Translational Medicine, Novartis Institutes for BioMedical Sciences
The preclinical assessment of a small molecule’s liability for QT interval prolongation is an essential part of the drug discovery process. Patch clamp assays for heterologously expressed recombinant cardiac ion channels are widely used in the pharmaceutical industry to evaluate potential drug-channel interactions. These assays are generally acute assessments and are not designed to detect indirect channel modulations that may result in QT prolongation. Despite the abundant literature demonstrating potential transcriptional, translational and post-translational mechanisms for indirect ion channel modulation, contribution of these mechanisms to drug-induced QT prolongation and/or arrhythmia propensity is not well understood. In this brief review, we discuss some potential mechanisms through which indirect ion channel modulation can produce QT prolongation and strategies for their early detection and mitigation.
Among the challenges for the pharmaceutical industry, declining research productivity and increasing research costs take a prominent position. This is often put in the context of efforts in the pharmaceutical industry to automate and “industrialise” research activities, combinatorial chemistry and High Throughput Screening being the most prominent examples. An argument is being put forward that the industry replaced scientists with robots and scientists’ ingenuity with mindless screening. It is then concluded that the investments into automation were misguided and led to a decline in research productivity.
MALDI FT-ICR MS platform for proteomics: Rationale for an offline approach and optimised implementation
MALDI FT-ICR MS platform for proteomics: Rationale for an offline approach and optimised implementation
A number of sophisticated approaches have been developed to study the structure and function of genes, including the whole-scale sequencing of entire organisms, global transcriptional profiling, and forward genetic studies. However, these techniques are ultimately limited by the fact that they only assess intermediates on the way to the protein products of genes that ultimately regulate biological processes[4,5].
The complexity of drug discovery faces many challenges; principally, the failure of drug candidates during the development process as a result of adverse effects or lack of efficacy. A key reason for this high attrition rate is that we are only just beginning to understand the complexity of the response(s) from a biological system to perturbations, such as a disease state or drug treatment. Subsequently, a deeper insight into the molecular mechanisms underlying both disease processes and drug action will ultimately contribute to increased productivity through the drug discovery process[1,2].
High content screening (HCS) is based on subcellular imaging using automated microscopy, in combination with automated image analysis. High content screening was first introduced over a decade ago as one of the promising new technologies, intended to address the bottleneck of secondary assays in the development of new drugs. Since then, the application has rapidly expanded throughout the entire drug discovery process, from target identification and validation, through to lead optimisation and detailed investigation of the mode of action.[1,2,3]
Non-coding RNAs (ncRNAs) consist of a growing heterogeneous class of transcripts defined as RNA molecules that lack any extensive “Open Reading Frame” (ORF) and function as structural, catalytic or regulatory entities rather than serving as templates for protein synthesis. While non-coding sequences make up only a small fraction of the DNA of prokaryotes, among eukaryotes, […]
One major cause of the late failure of drugs in development (i.e. attrition) is the lack of clinical safety of the compounds (accounting for approximately 30% of failures together with toxicology)1. One of the key elements is the off-target effects of the compounds, causing adverse drug reaction (ADRs).
Issue 3 2005, Past issues / 22 August 2005 / Craig S. Mickanin, Research Investigator and Mark A. Labow, Executive Director, Genomic and Proteomic Sciences, Novartis Institutes for BioMedical Research
Perhaps the most significant technological advancement in the study of gene function in the post-genome era has been the discovery that RNA interference (RNAi) can be exploited for depletion of endogenous mRNA in mammalian cells. As the pharmaceutical industry has fallen under intense pressure to both identify and validate high-quality drug targets, the lure of bona fide genome-wide functional analysis and target identification using small interfering RNA (siRNA) has fueled the interest in what can now be truly called ‘functional’ genomics.
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