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Proteins - Articles and news items

Automating the development of aptamer-based biological tools with Tecan

Automating the development of aptamer-based biological tools with Tecan

Supplier news / 24 February 2016 / Tecan

The ARNA Laboratory in Bordeaux, France, is using DNA and RNA aptamers to develop novel tools for biological applications…

New UV-Vis Spectrophotometer simplifies sample quality decisions

New UV-Vis Spectrophotometer simplifies sample quality decisions

Supplier news / 22 October 2015 / Thermo Fisher Scientific

Thermo Scientific NanoDrop One spectrophotometers designed to identify contaminants, providing accurate concentrations…

Record Attendance for Cambridge Healthtech Institute's Seventh Annual PEGS Europe Summit

Record attendance for Cambridge Healthtech Institute’s Seventh Annual PEGS Europe Summit

Supplier news / 16 October 2015 / CHI

Largest European Event for Biologics Returns to Lisbon from 2-6 November…

Mirus Bio: Development and Optimization of CHOgro® Transient Expression Technologies for High Titer Antibody Production in Suspension CHO Cells

Whitepaper: Development and optimization of CHOgro® transient expression technologies for high titer antibody production in suspension CHO cells

Whitepapers / 1 October 2015 / Mirus Bio

During early stage drug development, quickly obtaining relevant candidate proteins through transient transfection can accelerate drug discovery…

Sartobind® membrane adsorbers: the new design of capsules enables higher binding capacities and reduced void volumes

Improved membrane chromatography performance

Supplier news / 12 August 2015 / Sartorius

Redesigned Sartobind® membrane adsorber capsules offer higher binding capacities, reduced void volumes, less buffer consumption and lower operational costs…

ebi-005-eye

Clinical data on EBI-005 for the treatment of dry eye disease and allergic conjunctivitis presented at ARVO 2015

Industry news / 8 May 2015 / Victoria White

Eleven Biotherapeutics presented clinical data for EBI-005 for dry eye disease and allergic conjunctivitis at the ARVO 2015 Annual Meeting…

Recombinant protein

A history of recombinant protein technology in small molecule drug discovery

Issue 5 2014, Screening / 28 October 2014 / Rick Davies, Associate Director, AstraZeneca / Ian Hardern, Senior Research Scientist, AstraZeneca / Ross Overman, Associate Principal Scientist, AstraZeneca

Recombinant protein production is a prerequisite and essential component of most modern small molecule drug discovery programs. Target proteins are required to underpin screening, structural and mechanistic studies providing data that drives chemical design. From the initial establishment of recombinant protein production in the pharmaceutical industry in the 1980s, systems and technologies have evolved in step with developments in other areas to enable rapid production of many different target proteins, and their variants, specifically designed for their end use. This review describes the evolution of recombinant protein production over the past 30 years, tracking changes in technologies and working practices in relation to landmark changes in drug discovery strategies over that period…

FIGURE 1 Parties involved in the biomarker discovery and validation process. Medical Science is responsible for sample collection, pre-classification and storage in biobanks. Analytical Chemistry is responsible for developing sample preparation protocols and analytical platforms both for comprehensive biomarker discovery on low numbers of samples as well as for the targeted validation in large sample cohorts. Bioinformatics is responsible for performing the data pre-processing and statistical analysis as well as the validation of data and clinical information provided by the analytical and medical partners. A close collaboration and information exchange is essential for the success of biomarker research

Discovery and validation of protein biomarkers

Cancer Biology, Issue 3 2012 / 10 July 2012 / Péter Horvatovich & Rainer Bischoff, Analytical Biochemistry, Department of Pharmacy, University of Groningen

Biomarkers are biological characteristics that are objectively measured and evaluated as indicators of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention. Biomarkers can be used to determine disease onset, progression, efficacy of drug treatment, patient susceptibility to develop a certain type of disease or predict efficacy of treatment at a particular disease stage. Protein molecular biomarkers are particularly popular due to the availability of a large range of analytical instrumentation, which can identify and quantify proteins in complex biological samples. Proteins are key compounds in biosynthesis, cell, tissue and organ signalling and provide cell and tissue structural stability in living organisms. The primary protein sequences are encoded in the genome; however, their complex posttranslational modifications (PTMs) and three dimensional structures are fairly unpredictable from genomic information. In this mini-review, we will provide an overview of the current state, challenge and important aspects of protein biomarker discovery and validation…

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

microRNA manipulation as a host-targeted antiviral therapeutic strategy

Genomics, Issue 6 2011 / 13 December 2011 / 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 misexpression is known to occur in a range of human disease conditions and drugs based on modulating miRNA expression are now in development for treatment of cancer, cardiovascular, metabolic and inflammatory diseases. In the last six years, an increasing number of reports have also illuminated diverse roles of cellular miRNAs in viral infection and a miRNA-targeting therapy is currently in phase II clinical trials for treatment of the Hepatitis C virus. Here we review the literature related to miRNAs that regulate viral replication and highlight the factors that will influence the use of miRNA manipulation as a broader antiviral therapeutic strategy.

microRNAs (miRNA) are a class of small noncoding RNA that bind to messenger RNAs (mRNA) and regulate the amount of specific proteins that get expressed. These small RNAs are derived from longer primary transcripts that fold back on themselves to produce stem-loop structures which are recognised and processed by Drosha and co-factors in the nucleus followed by Dicer and co-factors in the cytoplasm, resulting in a ~ 22 nucleotide (nt) duplex RNA, for review see1,2. One strand of the duplex is preferentially incorporated into the RNA-induced silencing complex (RISC) where it then mediates binding to target mRNAs. These interactions lead to decreased protein getting produced from the transcript, due to RNA destabilisation and/or inhibited translation3 (Figure 1). miRNA-mRNA recognition generally requires perfect complementarity with only the first 6-8 nt of a miRNA, termed the ‘seed’ site4. Each miRNA therefore has the potential to interact with hundreds of target mRNAs3,4 and the majority of human protein-coding genes contain miRNA binding sites under selective pressure5. Therapeutic interest in miRNAs has been supported by studies in model organisms demonstrating key functions of individual miRNAs in cancer, cardiac disease, metabolic disease, neuronal and immune cell function6.

FIGURE 1 The rapid evolution of sequencing technologies. A. First generation Sanger sequencing technology. B. Second ‘Next’ generation massively parallel sequencing technology (454 Sequencing © Roche Diagnostics) C. Third ‘Next-Next’ generation single molecule, real-time sequencing technology. In the coming years, second or third generation technologies may develop to an extent where a human genome can be sequenced for a USD 1,000 in a matter of hours

DNA sequencing technologies and emerging applications in drug discovery

Genomics, Issue 6 2011 / 13 December 2011 / Nalini A.L. Mehta & David J. Dow, Molecular and Cellular Technologies, Platform Technology and Science, GlaxoSmithKline and Anthony M. Battram, Molecular and Cellular Technologies, Platform Technology and Science, GlaxoSmithKline & Department of Life Sciences, Imperial College London

In recent years, the development of Next Generation DNA Sequencing (NGS) technology has significantly impacted molecular biology research, resulting in many new insights and discoveries. NGS technology goes beyond traditional DNA sequencing with applications that reach across the central dogma of molecular biology from DNA to RNA and protein science. Drug discovery is beginning to benefit from the diversity of NGS, with applications in evidence across various therapeutic areas, such as oncology, immunology and infectious diseases.

DNA is the molecule of life, containing the information for the synthesis of RNA molecules and proteins, which in turn form structural components of the cell or catalyse essential biochemical processes. Understanding the sequence of DNA, which is made from the four basic building blocks or ‘nucleotides’, A,G,C and T, has resulted in great insights and discoveries in cellular biology, pathology and disease, culminating in the human genome project, which achieved the remarkable feat of determining the sequence of the three billion bases of the human genome.

The field of DNA sequencing has witnessed some key milestones in technology develop – ment since the description of the first revolutionary DNA sequencing techniques in 19771,2. The Sanger dideoxy sequencing method, discovered by the Nobel Laureate Fred Sanger, underwent the most significant improvements and became the first automated sequencing platform in the late 20th century. Advancements in the Sanger process were partly motivated by the advent of the USD 3 billion Human Genome Project, which required the development of high-throughput tech – niques3,4 (Figure 1A).

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

Lead discovery for targeting G protein-coupled receptors

Drug Targets, Issue 5 2011 / 19 October 2011 / 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 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…

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

Stabilisation of nanoparticles during freeze drying: The difference to proteins

Issue 4 2011, Lyophilisation / 31 August 2011 / 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 the amorphous protein molecule. The use of lyoprotectants has also been found to be beneficial to preserve the original particle size distribution of nanoparticles during freeze drying. Until today, it has been speculated that the predominant mechanism to suppress physical instabilities of such colloidal particle systems is their embedment in a rigid glass. Today, there are various types of colloidal particles used in drug development, and sometimes the scientific literature gives evidence that glass formation was not necessarily required for stabilisation during freezing thawing or even freeze drying. The purpose of this article is therefore to briefly provide the latest insight into potential stabilisation mechanisms when freeze drying nanoparticles, a key knowledge for rational formulation and process design for such systems.

 

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