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A selection of articles from European Pharmaceutical Review covering Proteomics and Proteases:
5 September 2014 • Marco Casteleijn & Dominique Richardson, University of Helsinki
Pharmaceutical biotechnology is big business; it currently consists of 1/6 of the total volume of the pharmaceutical market and continues to grow steadily. Expression of therapeutic proteins is mainly done in living cells, although ‘cell free protein synthesis’ (CFPS) or ‘in-vitro transcription translation’ (IVTT) is beginning to emerge as an alternative for commercial production. In this article we will highlight some of the more recent advances in protein expression systems for the production of pharmaceutical proteins. We will also discuss current trends in the engineering of pharmaceutical proteins with improved properties...
Pharmaceutical proteomics: a journey from discovery and characterisation of targets to development of high-throughput assays
15 December 2013 • Joerg Reinders, Institute of Functional Genomics, University of Regensburg
Proteomics has evolved during the last few years from a time-intensive, cost-intensive and hard-to-reproduce technique in basic research to a versatile and reliable tool in various areas of pharmaceutical research. The exploding progress in mass-spectrometry-compatible protein and peptide-separation methods led to the development of new approaches particularly suited for monitoring a multitude of specific targets in highly complex matrices in a highly sensitive, specific and parallel fashion. These new technologies have caused a paradigm shift in proteomics from mostly gel-based, hypothesis-generating studies towards fast, cost-effective and mostly LC-MS-based assays. Therefore, proteomics emerges for pharmaceutical researchers aiming to identify and verify proteinaceous biomarkers as proteomics technology comes of age...
Proteases: How naturally occurring inhibitors can facilitate small molecule drug discovery for cysteine proteases
20 August 2013 • Sheraz Gul, Vice President and Head of Biology, European ScreeningPort GmbH
Cysteine proteases are expressed ubiquitously in the animal and plant kingdom and are thought to play key roles in maintaining homeostasis. The aberrant function of cysteine proteases in humans are known to lead to a variety of epidermal disease states such as inflammatory skin disease. In marked contrast, the serine proteases have been most widely implicated in disease states, including hypertension, periodontisis, AIDS, thrombosis, respiratory disease, pancreatitis and cancer, and a number of their inhibitors have been approved for clinical use.
13 June 2013 • Thierry Le Bihan, SynthSys and Institute of Structural and Molecular Biology, University of Edinburgh
In recent years, mass spectrometry (MS) based proteomics has moved from being a qualitative tool (used to mainly identify proteins) to a more reliable analysis tool, allowing relative quantitation as well as absolute quantitation of a large number of proteins. However, the developed quantitative methods are either specific for certain types of samples or certain types of mass spectrometers. In some cases, developing expertise on how to use a given method may take a long time and the use of these methods is therefore limited to few laboratories. Other quantitative methods are suitable for simple standard protein mixes which are far from the complexity of real samples. As a consequence, the number of available quantitative methods is high and choosing the right one is challenging.
18 April 2013 • Pedro R. Cutillas, MRC Clinical Sciences Centre, Imperial College London
Not all cancer patients, even those with the same tumour type, respond to therapy equally well. An understanding of this heterogeneity at the molecular level is crucial for further advances in the development of cancer therapies. Discerning the mechanisms of cancer heterogeneity will lead to a better selection of the most appropriate therapy for each patient and to an improvement in therapeutic outcomes. The success of such personalised cancer therapies requires biomarkers that can be used to stratify patients based on the likelihood that they may respond a particular drug or therapy1. This article discusses the rationale of using proteomics approaches to characterise such biomarkers.
10 July 2012 • Paul C. Guest, Department of Chemical Engineering and Biotechnology, University of Cambridge and Sabine Bahn Department of Chemical Engineering and Biotechnology, University of Cambridge & Department of Neuroscience, Erasmus Medical Centre
Pharmaceutical companies are under increasing pressure to improve their efficiency and returns on drug discovery projects. This is a daunting task considering that the average drug costs approximately one billion US dollars to develop and takes around 12 years from initial discovery to reach the market1. In addition, approximately 70 per cent of drugs fail to recover their research and development costs and around 90 per cent fail to provide a satisfactory return on investment. Therefore, minimising risk is one of the most important aims in pharmaceutical discovery programs today. There are now efforts to establish standard operating procedures to navigate through these problems and, at the same time, meet the regulatory demands. To facilitate this process, the regulatory health authorities have encour aged the incorporation of biomarkers into the drug discovery pipeline and the Food and Drug Administration (FDA) has called for efforts to modernise and standardise approaches for the delivery of more effective and safer drugs2. Proteomics is the most applicable tech - nology for implementing biomarker app - roaches in drug discovery given that virtually all existing drug targets are proteins3. Proteomics is a systems approach for the global study of protein expression changes4.
19 October 2011 • Ross Chawner and Claire E. Eyers, Michael Barber Centre for Mass Spectrometry, University of Manchester
Identification of protein biomarkers and the evaluation of changes in protein expression following drug treatment rely on both the generation of peptides from cellular proteins, and the acquisition and interpretation of spectra generated by tandem mass spectrometry (MS/MS). Acquisition of MS/MS spectra in a datadependent manner means that a significant number of the protein fragments (peptides) generated are never actually subjected to MS/MS1. Moreover, only a small proportion of acquired MS/MS spectra are ever interpreted, despite the large number of tools for the automated analysis of such data. Furthermore, many fragment ions are simply ignored during data analysis, in large part because automated search engines do not ‘look’ for all potential fragmentation products, and also because we simply still do not sufficiently understand the mechanisms of gas-phase peptide fragmentation to fully interpret the spectra (most likely a combination of the two). The end result is that even though proteome coverage is increasing in large-scale analyses, we are still a long way from the ideal of ‘complete’ proteome analysis.
16 February 2011 • Hubert Hondermarck, Professor and head of U908 INSERM research unit – Growth factor signalling in breast cancer – functional proteomics, University of Lille
The recent progresses in the field of proteomics now enable large scale, high throughput, sensitive and quantitative protein analysis. Therefore, applying proteomics in clinical oncology becomes realistic. From the analysis of cell cultures to biological fluids and tumour biopsies, proteomic investigations of cancers are flourishing and new candidate biomarkers and therapeutic targets are slowly emerging. In the meantime, what we know of the cancer proteome is also an evolving figure that is progressively unveiled. Given the multiparametric nature and diversity of cancers, it should not be underestimated that a great deal of time and effort will be necessary for translating that knowledge into practical applications in oncology.
22 February 2010 •
Innovative drug delivery technologies are key components of drug development, with commercial and intellectual values. PEGylation is an excellent example of a delivery system that has scientific and multi- billion dollar commercial importance due to the remarkable improvement in the circulatory half lives of therapeutics, especially for proteins and peptides but even for small molecule pharmaceuticals. Beginning with a brief introduction to the pharmaceutical advantages of PEGylated therapeutics, the authors review the development of this technology over the past four decades in terms of conjugation chemistry, poly(ethylene glycol) structure and process considerations, and conclude that improved, versatile and generic production methods are required to meet the growing demands of the pharmaceutical market...
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