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Proteomics - Articles and news items
Pharmaceutical proteomics: a journey from discovery and characterisation of targets to development of high-throughput assays
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…
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.
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.
Issue 3 2012, Proteomics / 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.
Chromatography, Issue 2 2012, Supplements / 25 April 2012 / Ana Rita Angelino, Min Yang, Tasso Miliotis, Constanze Hilgendorf, Anthony Bristow, George McLeod, Detlev Hochmuth, Alessandro Baldi, Gary Harland
Mass spectrometry in drug discovery – Proteomics, small molecules and metablomics.
Quantification of membrane drug transporters and application in drug discovery and development.
Mass spectrometry leaders roundtable.
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.
Issue 1 2011, Proteomics / 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.
Deciphering crude proteomes in the quest for candidate biomarker signatures for disease diagnostics, prognostics and classifications has proven to be challenging using conventional proteomic technologies. In this context, affinity protein microarrays, and in particular recombinant antibody microarrays, have recently been established as a promising approach within high-throughput (disease) proteomics1-3. The technology will provide miniaturised set-ups capable of profiling numerous protein analytes in a sensitive, selective and multiplexed manner.
Chromatography, Issue 5 2010 / 29 October 2010 / Brian Flatley Dept of Chemistry, University of Reading, Reading and Harold Hopkins Dept of Urology, Royal Berkshire NHS Foundation Trust Hospital, Reading and Peter Malone Harold Hopkins Dept of Urology, Royal Berkshire NHS Foundation Trust Hospital, Reading and Rainer Cramer Dept of Chemistry, University of Reading, Reading
Each year, approximately 10,000 men in the UK die as a result of prostate cancer (PCa) making it the third most common cancer behind lung and breast cancer. Worldwide, more than 670,000 men are diagnosed every year with the disease1. Current methods of diagnosis of PCa mainly rely on the detection of elevated prostate-specific antigen (PSA) levels in serum and/or physical examination by a doctor for the detection of an abnormal prostate. PSA is a glycoprotein produced almost exclusively by the epithelial cells of the prostate gland2. Its role is not fully understood, although it is known that it forms part of the ejaculate and its function is to solubilise the sperm to give them the mobility to swim. Raised PSA levels in serum are thought to be due to both an increased production of PSA from the proliferated prostate cells, and a diminished architecture of affected cells, allowing an easier distribution of PSA into the wider circulatory system.
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 […]
The pharmaceutical industry continues to experience a high attrition rate during the latter stages of small molecule therapeutic development, most disappointingly during the late, and highly expensive stages of Phase II and Phase III trial1. If left unchecked, it is likely that this late-stage failure in drug development will only increase the already staggering cost of getting pharmaceuticals to market. The failure of drugs at this stage in development occurs primarily because of problems with toxicity and/or failure to produce a significant effect in whole animal models (lack of efficacy)1. The increasingly popular approach of systems biology is perceived by many as a potential solution for overcoming these problems, enabling the design of effective, safe therapeutics on a realistic R&D budget.
There are compelling reasons for regularising the capture and description of proteomics data. Adhering to community-consensus specifications for the annotation of data sets can increase confidence in results and the conclusions drawn upon them, and supports data re-use; working with standard formats and vocabularies can raise efficiency and facilitates sophisticated approaches to data handling and analysis. The Human Proteome Organisation’s Proteomics Standards Initiative (HUPO PSI) is a standards generating body comprising diverse members of the proteomics community and related trades. It develops reporting guidelines, data formats and vocabulary terms with which to describe the components of a proteomics experiment. This article briefly explores the benefits accruing to the use of reporting standards, for academics and for those in a commercial setting; describes HUPO PSI, its products and the status quo with respect to compatible tools and databases; and closes by pulling back to consider multi-domain investigations in the life sciences.