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Going with the flow
November 2010
by Lloyd Dunlap  |  Email the author
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SAN JOSE, Calif.—Building on a two-and-a-half-year-old relationship, Thermo Fisher Scientific Inc. and Proteome Sciences PLC will collaborate to deliver innovative products for protein biomarker research. Specifically, the Thermo Fisher Scientific Biomarker Research Initiatives in Mass Spectrometry (BRIMS) Center will work with Proteome Sciences to further develop quantitative proteomic workflows, including reagents, hardware and software for biomarker discovery and validation.

Proteome Sciences will combine Thermo Scientific mass spectrometry technology with its integrated PS Biomarker Services workflow that is powered by tandem mass tag (TMT) reagents. Proteome Sciences has installed Thermo Scientific LTQ Orbitrap Velos and TSQ Vantage mass spectrometer systems at its research laboratories in Frankfurt, Germany, to extend its biomarker discovery and validation workflows.

"Velos is the workhorse for biomarker discovery," with the speed, accuracy and high sensitivity required to survey more of the proteome, says Dr. Ian Pike, COO of Proteome Sciences. "Now we can get deeper and see more."

"The Thermo Scientific Orbitrap LTQ Velos mass spectrometer, with its unique combination of HCD (high-energy C-trap dissociation) and ETD (electron transfer dissociation) fragmentation, will allow us to extend the scope of proteomic services we offer to customers," Pike says. "When using the TSQ Vantage high-sensitivity triple quadrupole mass spectrometer in combination with our proprietary TMT tandem mass tag technology for assay development, we can offer the most integrated biomarker discovery, qualification and assay validation workflows in the industry. We have already successfully used TMT technology to develop mass spec assays for blood biomarkers in Alzheimer's disease, and are extending our coverage for other proprietary biomarkers in cancer and brain damage. Access to these resources is available through our PS Biomarker Services Division."

The companies have recently expanded the range of products through the launch of a cysteine-reactive sixplex TMT set and an anti-TMT antibody used to enrich labeled peptides that improve sensitivity and breadth of coverage for many low-abundance proteins. Clinical biomarkers tend to be in the low abundance range, Pike notes.

Dr. John Rogers, manager of Thermo Scientific Pierce Proteomics Reagents R&D, adds: "We have been aggressively pushing the capabilities of the TMT technology to take full advantage of the outstanding mass spec performance of the core tag structure. The introduction of cysTMT reagents and an immobilized antibody to the TMT reagent core structure is just the start of the process, and further TMT products with additional reactive selectivity are in the pipeline."

Proteome Sciences has been working with team members at the BRIMS Center to adapt workflows for isotope dilution mass spectrometry assays based on the technique of selected reaction monitoring (SRM). With the installation of the highly sensitive TSQ Vantage triple quadrupole mass spectrometer and Thermo Scientific Accela LC system at its Frankfurt labs, Proteome Sciences will expand its relationship with BRIMS to develop its proprietary biomarker assays in Alzheimer's disease and cancer for clinical research applications.

"The ability to use the different forms of TMT technology in discovery and then for biomarker candidate verification is extremely powerful," comments Pike. "More TMT reaction chemistries will widen the scope of our biomarker research and, in combination with the ongoing developments in Thermo Scientific mass spectrometer platforms, will bring even the relatively low-abundant proteins within reach of MS assays."

Proteome Sciences started the move toward routinely using SRM assays for biomarker candidate identification in 2008. Whereas immunoassays are slow and expensive to develop and have to be done one marker at a time, SRM methods have the advantage of being both rapid and relatively inexpensive to set up. Many proteins can be measured in a single test. Proteome Sciences has set up the PS Biomarker Services Division to provide a seamless workflow where isobaric TMT reagents are used to increase performance in discovery and then isotopic TMT reagents are used to rapidly set up SRM assays for candidate biomarker identification. This is supported by the Proteotype DB database of more than 4,500 human and 1,500 rodent proteins that Proteome Sciences has identified by mass spectrometry during its 10 years of internal research and development.



Minnesota researchers use Thermo Fisher Scientific screening collection to identify anti-inflammatory compound candidate

TINTAGEL, U.K.—Thermo Fisher Scientific Inc., the world leader in serving science, also recently announced that its Maybridge HitFinder screening compound collection has helped scientists at the University of Minnesota identify and characterize a small-molecule inhibitor that holds promise for the development of anti-inflammatory drugs.

The HitFinder collection is an offering of drug-like screening compounds that uses an industry-standard clustering algorithm to select a statistically representative sample of the full collection. All compounds fit Lipinski guidelines for "drug-likeness" and have purity greater than 90 percent. Additionally, Thermo Fisher says they have been selected to be non-reactive, ensuring fewer false positives and higher quality results.

Prof. David Bernlohr, head of the Department of Biochemistry, Molecular Biology and Biophysics at the university, and his team used the HitFinder collection in studies of fatty-acid-binding protein (FABP) inhibitors. According to the researchers, the collection was an invaluable tool in helping the team identify several compounds that may potentially block FABP. Ultimately, from this library they identified HTS01037, a pan-specific FABP inhibitor with broad anti-inflammatory properties.

From this initial study, the Bernlohr group has been able to expand its analysis of FABP inhibitors and use them to probe FABP function in a variety of cells and systems.

"Molecular disruption of the lipid carrier AFABP/ap2 in mice has been found to result in improved insulin sensitivity, protection from atherosclerosis, as well as reduction in LPS-stimulated inflammation," says Bernlohr. "We were therefore interested in investigating the efficacy of small-molecule inhibitors in defining the mechanisms of AFABP/aP2 action that could ultimately deliver a pharmacologically beneficial compound. To achieve this, we required a good quality chemical screening library as an essential starting point."

 
Code: E111017

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