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Manchester, United Kingdom

Grant
Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: NMP-2007-1.1-1 | Award Amount: 5.44M | Year: 2008

More than 50% of all drug targets are membrane proteins; new research tools to screen function of membrane drug targets are therefore expected to open up new avenues for original drug development. The proposed project addresses the need of the pharmaceutical industry for new technologies for reliable and efficient screening of membrane proteins as drug targets. Most critical current aspects of membrane protein assays are (a) the lack of reliable procedures to immobilize membrane proteins on sensor surfaces in a format suitable for label-free high-throughput screening of drug candidates; (b) the need for downscaling assay formats to accelerate functional screening; and (c) the feasibility of reading out the diverse functions of membrane proteins. The partners with highly complementary expertise and experience of working together will develop platforms for functional membrane protein assays by integration of the most recently gained knowledge and techniques. The key concepts of the platforms include (a) exploitation of nanoporous substrates to enhance the stability of supported proteolipid membranes and their integration in a sensor chip format; (b) nanoscale surface modifications for directed self-assembly of proteolipid structures on chip; and (c) self-assembly of proteolipid membranes onto nano-sized sensor structures from proteoliposomes, and demonstration of the functionality in quantitative drug candidate screening assays suitable for commercial applications. The project is expected to make a substantial contribution to (a) improved understanding of lipid membrane and membrane protein interaction with designed nanoenvironments; (b) development of prototype products and intellectual property related to membrane protein sorting and handling; (c) new compounds for functionalization of biosensor applications; (d) cost-effective array-based concepts for nanoplasmonic and electrochemical sensing; and (e) functional assays for membrane protein drug targets.


Grant
Agency: Cordis | Branch: FP7 | Program: CP | Phase: ICT-2007.3.5 | Award Amount: 3.36M | Year: 2008

InTopSens is a multidisciplinary project involving the emerging fields of photonics structures, electronics, fluidics and bio-chemistry, to contribute to the development of high value sensor technology. This objective will be addressed through the demonstration of a compact polymer and silicon-based CMOS-compatible photonics sensor system. It integrates two label-free biomolecular recognition photonic sensor technologies with sensitivities as low as 0.1ng per ml, state-of-the-art in label-free integrated optical biosensors, with novel coupling technology that will permit very high integration of hundreds of sensing areas on a 1mm2 photonics chip. This offers the further advantageous possibility of assaying several parameters simultaneously leading to further increases in the reliability and reductions in the measurement uncertainty of a diagnostic over single-parameter assays. The novel diagnostic technology of the InTopSens device has the potential to be fast and easy to use, making routine screening or monitoring of bacteria more cost-effective. The ultimate target of InTopSens is to demonstrate the feasibility of a rapid diagnostic test for sepsis at point of care. From the introduction onto the chip of a large drop of blood (some 5ml) it will have after 5-10 mins a yes/no to the presence of bacteria and after less than 30mins an antibiotic resistance profile of the infecting bacteria. Some 120 sensing areas/datapoints are needed to identify this profile and as such due to the very high integration up to 250 assays can be integrated onto a 1mm2 chip for the same bacteria for higher sensitivity/selectivity or for other bacteria. A final prototype consisting of a packaged biochip will be used on clinical samples in order to detect the sepsis bacteria and determine their resistance to antibiotics.


Coan K.E.D.,Novartis | Swann M.J.,Farfield | Ottl J.,Novartis
Analytical Chemistry | Year: 2012

In early drug discovery, knowledge about ligand-induced conformational changes and their influence on protein activity greatly aids the identification of lead candidates for medicinal chemistry efforts. Efficiently acquiring such information remains a challenge in the initial stages of lead finding. Here we investigated the application of dual polarization interferometry (DPI) as a method for the real-time characterization of low molecular weight (LMW) ligands that induce conformational changes. As a model system we chose calmodulin (CaM), which undergoes large and distinct structural rearrangements in response to calcium ion and small molecule inhibitors such as trifluoperazine (TFP). We measured concentration-dependent mass, thickness, and density responses of an immobilized CaM protein layer, which correlated directly with binding and conformational events. Calcium ion binding to CaM induced an increase in thickness (≤0.05 nm) and decrease in density (0.03 g/cm 3) whereas TFP induced an increase in both thickness (0.05 nm) and density (0.01 g/cm 3). The layer measurements reported here show how DPI can be used to assess and differentiate ligands with distinct structural modes of action. © 2011 American Chemical Society.


Hirst D.J.,Monash University | Lee T.-H.,Monash University | Swann M.J.,Farfield | Aguilar M.-I.,Monash University
Analytical Chemistry | Year: 2013

Kinetic analysis of peptide-membrane interactions generally involves a curve fitting process with no information about what the different curves may physically correspond to. Given the multistep process of peptide-membrane interactions, a computational method that utilizes physical parameters that relate to both peptide binding and membrane structure would provide new insight into this complex process. In this study, kinetic models accounting for two-state and three-state mechanisms were fitted to our previously reported simultaneous real-time measurements of mass and birefringence during the binding and dissociation of the peptide HPA3 (Hirst, D.; Lee, T.-H.; Swann, M.; Unabia, S.; Park, Y.; Hahm, K.-S.; Aguilar, M. Eur. Biophys. J. 2011, 40, 503-514); significantly, the mass and birefringence are constrained by the same set of kinetic constants, allowing the unification of peptide binding patterns with membrane structure changes. For the saturated phospholipid dimyristoyl- phosphatidylcholine (DMPC) the two-state model was sufficient to account for the observed changes in mass and birefringence, whereas for the unsaturated phospholipid 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) the two-state model was found to be inadequate and a three-state model gave a significantly better fit. The third state of interaction for POPC was found to disrupt the bilayer much more than the previous two states. We propose a hypothesis for the mechanism of membrane permeabilization based on the results featuring a loosely bound first state, a tightly bound second state, and a highly membrane-disrupting third state. The results demonstrate the importance of the difference in membrane fluidity between the gel phase DMPC and the liquid crystal phase POPC for peptide-membrane interactions and establish the combination of DPI and kinetic modeling as a powerful tool for revealing features of peptide-membrane interaction mechanisms, including intermediate states between initial binding and full membrane disruption. © 2013 American Chemical Society.


Patent
Farfield | Date: 2014-04-30

This disclosure is directed to broadband polarization diversity antennas. In one aspect, a polarization diversity antenna includes a baseboard with a baseboard-feed line located on a first surface. The baseboard-feed line includes a serpentine meander-line portion. The antenna also includes an antenna-array board with two or more antenna elements arranged in a series. The antenna-array board is attached to the first surface with the serpentine meander-line portion located between an edge of the antenna-array board and the baseboard. Each antenna element is connected to the serpentine meander-line portion via an antenna-feed line located on the antenna-array board. The antenna array provides two dimensional polarization broadcasting and receiving of electromagnetic radiation. In another aspect, a notch antenna is formed on an opposing second surface of the baseboard opposite the antenna-array board in order to provide three-dimensional polarization broadcasting and receiver of electromagnetic radiation.

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