3D structure opens new avenue for drug discovery

The enzyme SHIP2, which plays a major role in cell signalling, has attracted particular attention due to its role in the negative regulation of insulin signalling and is thought to be involved in type-2 diabetes, obesity and cancer. Previous attempts to crystallise the enzyme with its natural substrate were unsuccessful, so scientists at Bath designed a new synthetic inhibitor as a mimic and with their European colleagues solved the X-ray crystal structure of a key fragment of SHIP2 bound to this compound.

The research, recently published in the leading international journal ACS Chemical Biology, was a collaborative project carried out by an international group of scientists based at the Karolinska Institutet in Stockholm Sweden, Nanyang University Singapore, the Université Libre de Bruxelles in Belgium and the University of Bath.

The scientists also undertook computational molecular dynamics on the complex, and discovered a flexible loop region of the protein that may close over the compound during binding. The researchers hope that targeting such a closed complex could provide a new strategy for the design of small-molecule drugs against SHIP2.

Professor Barry Potter, who led the enterprise together with his Wellcome Trust–funded Bath colleagues Drs Steve Mills, Andrew Riley, Gyles Cozier and Mark Thomas, said: “Such interdisciplinary collaboration represents a real route to early progress in drug discovery at a time when the global pharmaceutical industry is restructuring and looking more than ever towards academic-industry partnerships for early stage drug discovery, rather than in-house R&D.

“These data further reinforce use of a new class of synthetic molecule that we have pioneered at Bath for several years, for co-crystallisation studies.

“This work emphasises the strength of Medicinal Chemistry at the University of Bath and demonstrates that academic scientists can play a key role in drug discovery, particularly at early and innovative stages.”

The next step will be to design in silico related, but more drug-like, compounds that might bind to the closed complex of the SHIP2 enzyme. The researchers hope that others will use their work as a starting point to design such novel drug candidates.

More information: http://pubs.acs.or … 21/cb200494d

Provided by University of Bath (news : web)

Stabilizing entangled spaghetti-like materials: Controling forces between oppositely charged polymers opens new route for gene therapy vectors

Gene therapy can only be effective if delivered by a stable complex molecule. Now, scientists have determined the conditions that would stabilise complex molecular structures that are subject to inherent attractions and repulsions triggered by electric charges at the surfaces of the molecules, in a study about to be published in the European Physical Journal E, by Valentina Mengarelli and her colleagues from the Solid State Physics Laboratory at the Paris-Sud University in Orsay, France, in collaboration with Paris 7 and Évry Universities scientists.

The authors studied soluble complexes made of negatively charged DNA or another negatively charged polymer -- polystyrene-sulfonate (PSSNa) -- and a so-called condensation agent, which is a negatively charged polymer, known as linear polyethyleneimine (PEI). PEI participates in the condensation process by tying onto a molecule such as DNA, like tangled hair, to form an overall positively charged DNA/polymer complex structure. Previous research focused mainly on non-soluble complexes, while the few attempts at focusing on soluble complexes dealt either with smaller polymers or those with a weaker electric charge, which may therefore be easier to stabilise.

The French team thus confirmed experimentally that the complexation process does not depend on the rigidity of the original molecule, be it DNA or PSSNa, but on the positive/negative electric charge ratio and on the polymer concentrations. It is the interactions between electrically charged parts within the complex that govern its properties. When the condensation agent is in excess, the positively charged complex is then attracted to negatively charged biological cell membranes. This could be used to deliver the DNA into a targeted cell nucleus as part of gene therapy treatment.Future work will focus on using long DNA molecules and novel polymers to form complexes of controlled size and electric charge for gene therapy.

Story Source:

The above story is reprinted from materials provided by Springer.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

Mengarelli V, Auvray L, Pastré D, and Zeghal M,. Charge inversion, condensation and decondensation of DNA and Polystyrene sulfonate by polyethylenimine. European Physical Journal E (EPJE), 2011; 34, 127 DOI: 10.1140/epje/i2011/11127-3

Unprecedented formation of a boron-boron covalent bond opens a new corner of chemistry

The compound that the researchers made features two boron atoms held together by a shared pair of electrons. For other elements—carbon, for example—that would be a typical bond, but electron-poor boron tends to prefer a more complex arrangement. In the boron compound diborane (B2H6), for example, two boron atoms are bridged by hydrogen atoms, with each boron–hydrogen–boron bond sharing a single pair of electrons across three atoms rather than the usual two.

Theory has long predicted that by pumping extra electrons into a compound such as diborane, the boron–hydrogen–boron structure should break down to form a boron–boron single bond. Until now, however, all such attempts to make and isolate such a structure had failed, instead generating clusters or single boron species.

Matsuo and Tamao’s strategy for generating the boron–boron bond was to start with a borane precursor where each boron atom was fitted with a bulky side-group known as an Eind group. The researchers suspected that previous attempts probably succeeded in generating the boron–boron single bond but failed to protect that structure from quickly falling apart through over-reaction. Using the bulky side-groups, they were able to block these over-reaction processes, and successfully isolate the desired boron–boron single bond (Fig. 1).

Having discovered a new way to make the boron–boron bond, the next step will be to assess its chemistry and reactivity, and to explore related structures, says Shoji. The bond has already proved to be relatively stable: the team has shown that if protected from air and moisture, the boron–boron compound can be stored for months at ambient temperature. It can also be converted into a three-membered ring, in which a bridging hydrogen atom is the third member, forming a molecule with potentially useful properties. “We think that the hydrogen-bridged boron–boron bond has a double-bond character,” says Matsuo. “We would like to explore the new reaction chemistry of multiply bonded boron species.”

More information: Shoji, Y., et al. Boron–boron ?-bond formation by two-electron reduction of a H-bridged dimer of monoborane. Journal of the American Chemical Society 133, 11058–11061 (2011).

Provided by RIKEN (news : web)

Soft memory device opens door to new biocompatible electronics

 Researchers from North Carolina State University have developed a memory device that is soft and functions well in wet environments -- opening the door to a new generation of biocompatible electronic devices.

"We've created a memory device with the physical properties of Jell-O," says Dr. Michael Dickey, an assistant professor of chemical and biomolecular engineering at NC State and co-author of a paper describing the research.

Conventional electronics are typically made of rigid, brittle materials and don't function well in a wet environment. "Our memory device is soft and pliable, and functions extremely well in wet environments -- similar to the human brain," Dickey says.

Prototypes of the device have not yet been optimized to hold significant amounts of memory, but work well in environments that would be hostile to traditional electronics. The devices are made using a liquid alloy of gallium and indium metals set into water-based gels, similar to gels used in biological research.

The device's ability to function in wet environments, and the biocompatibility of the gels, mean that this technology holds promise for interfacing electronics with biological systems -- such as cells, enzymes or tissue. "These properties may be used for biological sensors or for medical monitoring," Dickey says.

The device functions much like so-called "memristors," which are vaunted as a possible next-generation memory technology. The individual components of the "mushy" memory device have two states: one that conducts electricity and one that does not. These two states can be used to represent the 1s and 0s used in binary language. Most conventional electronics use electrons to create these 1s and 0s in computer chips. The mushy memory device uses charged molecules called ions to do the same thing.

In each of the memory device's circuits, the metal alloy is the circuit's electrode and sits on either side of a conductive piece of gel. When the alloy electrode is exposed to a positive charge it creates an oxidized skin that makes it resistive to electricity. We'll call that the 0. When the electrode is exposed to a negative charge, the oxidized skin disappears, and it becomes conducive to electricity. We'll call that the 1.

Normally, whenever a negative charge is applied to one side of the electrode, the positive charge would move to the other side and create another oxidized skin -- meaning the electrode would always be resistive. To solve that problem, the researchers "doped" one side of the gel slab with a polymer that prevents the formation of a stable oxidized skin. That way one electrode is always conducive -- giving the device the 1s and 0s it needs for electronic memory.

The paper was published online July 4 by Advanced Materials. The paper was co-authored by NC State Ph.D. students Hyung-Jun Koo and Ju-Hee So, and NC State INVISTA Professor of Chemical and Biomolecular Engineering Orlin Velev. The research was supported by the National Science Foundation and the U.S. Department of Energy.

NC State's Department of Chemical and Biomolecular Engineering is part of the university's College of Engineering.

Story Source:

The above story is reprinted (with editorial adaptations) from materials provided by North Carolina State University.

Journal Reference:

Hyung-Jun Koo, Ju-Hee So, Michael D. Dickey, Orlin D. Velev. Towards All-Soft Matter Circuits: Prototypes of Quasi-Liquid Devices with Memristor Characteristics. Advanced Materials, 2011; DOI: 10.1002/adma.201101257

AkzoNobel opens €7 million fire protection R&D facility

06-10-2011: AkzoNobel opened a €7 million state-of-the-art fire protection laboratory at its Felling site in the UK, part of a major €10 million investment in research, development and innovation (RD&I) which will create around 40 new jobs.

The lab will be operated by the company's Marine and Protective Coatings business. The global market is growing rapidly due to increasingly stringent fire protection regulations worldwide, with forecasters expecting demand to double by 2018.

"This modern facility will help us to drive innovation and deliver cutting-edge performance coatings technology in line with what our customers demand," said Graeme Armstrong, the company's Executive Committee member responsible for RD&I. "We have installed furnaces on a scale which will test what conditions our coatings materials have to withstand, enabling us to supply our customers with technically sophisticated solutions that are proven and commercially viable."

The new facility is the latest in a series of RD&I investments by AkzoNobel at the Felling site, which employs more than 950 people. Earlier this year, a €2 million lab for powder coatings polymer research and a €1.4 million corporate research laboratory were inaugurated at the location.

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Next-generation computers: Advance in microchannel manufacturing opens new industry applications

Engineers at Oregon State University have invented a new way to use surface-mount adhesives in the production of low-temperature, microchannel heat exchangers -- an advance that will make this promising technology much less expensive for many commercial applications.

This type of technology will be needed, researchers say, in next-generation computers, lasers, consumer electronics, automobile cooling systems, fuel processors, miniature heat pumps and more.

New industries and jobs are possible. A patent has been applied for, the findings reported in the Journal of Manufacturing Processes, and the university is seeking a partner for further commercial development.

"Even though microchannel arrays have enormous potential for more efficient heat transfer and chemical reactions, high production costs have so far held back the broad, mainstream use of the technology," said Brian Paul, a professor in the OSU School of Mechanical, Industrial and Manufacturing Engineering.

"In certain applications, this new approach has reduced material costs by 50 percent," Paul said. "It could cut production bonding costs by more than 90 percent, compared to existing approaches to microchannel lamination. And the use of surface-mount adhesives is directly translatable to the electronics assembly industry, so there is less risk going to market.

"This type of manufacturing research could enable a microchannel revolution," he said.

Microchannels, the diameter of a human hair, can be patterned into the surface of a metal or plastic, and can be designed to speed up the heat exchange between fluids, or the mixing and separation of fluids during chemical reactions. The accelerated heat and mass transfer leads to smaller heat exchangers and chemical reactors and separators, such as a portable "home dialysis" system that evolved out of previous OSU research.

Cost and production issues, however, have until now constrained the wider industrial use of this technology. The new manufacturing technique developed at OSU should help change that.

"We have demonstrated the use of surface-mount adhesives to create microchannels on a wide variety of metals, including aluminum, which is very cheap," said Prawin Paulraj, an OSU doctoral candidate and lead author on the recent study. "Bonding aluminum is difficult with conventional techniques."

These very thin pieces of patterned metal -- akin to aluminum foil -- can be bonded one on top of another to increase the number of microchannels in a heat exchanger, and the amount of fluid that can be processed. Creation of laminated microchannel arrays in a wide variety of materials is possible, including aluminum, copper, titanium, stainless steel and other metals.

"In computers and electronics, the heat generated by the electrical circuit is a limiting factor in how small you can make it," Paulraj said. "Microchannel process technology provides an efficient way to cool computers and consumer electronics, and make them even smaller."

The adhesives are limited in temperature to about that of boiling water. The researchers say that possible uses might include radiators to cool an automobile engine or small, very efficient heat pumps for efficient air conditioning within buildings.

This research was conducted at the Microproducts Breakthrough Institute, a user facility of the Oregon Nanoscience and Microtechnologies Institute.

University officials are now seeking a commercial partner in private industry to continue development and marketing of the technology, according to Denis Sather, a licensing associate in the OSU Office for Commercialization and Corporate Development.

Story Source:

The above story is reprinted from materials provided by Oregon State University.

Journal Reference:

Prawin, Paulraj and Paul, Brian K. Metal Microchannel Lamination Using Surface Mount Adhesives for Low-Temperature Heat Exchangers. Journal of Manufacturing Processes, Mar 12, 2011 [link]

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New laser technique opens doors for drug discovery

 Researchers have demonstrated that a new laser technique can be used to measure the interactions between proteins tangled in a cell's membrane and a variety of other biological molecules. These extremely difficult measurements can aid the process of drug discovery.

Scientists estimate that about 30 percent of the 7,000 proteins in a human cell reside in the cell's membrane, and that these membrane proteins initiate 60 to 70 percent of the signals that control the operation of the cell's molecular machinery. As a result, about half of the drugs currently on the market target membrane proteins.

Despite their importance, they are difficult to study. Individual membrane proteins are extremely hard to purify, so scientists have very little structural information about them. In addition, existing methods to measure their activity have serious limitations. Most existing assays remove the membranes from their natural environment or modify them in a variety of different ways, such as attaching fluorescent labels, in order to analyze membrane protein activity.

"In addition to being expensive and time-consuming, these modifications can affect the target membrane's function in unpredictable ways," said Vanderbilt Professor of Chemistry Darryl Bornhop, who developed the new technique.

By contrast, in an article published online in the journal Nature Biotechnology, Bornhop's research group and their collaborators at The Scripps Research Institute report that the laser-based technique, called backscattering interferometry (BSI), can precisely measure the binding force between membrane proteins and both large and small molecules in a natural environment.

This is a powerful tool and a major advance in measuring membrane protein interactions," said Lawrence Marnett, director of the Vanderbilt Institute of Chemical Biology. "This is a powerful tool and a major advance in measuring membrane protein interactions," said Lawrence Marnett, director of the Vanderbilt Institute of Chemical Biology. Marnett, who is also Mary Geddes Stahlman Professor of Cancer Research, was not involved in the study but is planning on collaborating with the Bornhop group.

Lasers aid measurement

BSI is deceptively simple. It measures the binding force between two molecules mixed in a microscopic liquid-filled chamber by shining a red laser like those used in barcode scanners through it. When the geometry of the chamber is correct, the laser produces an interference pattern that is very sensitive to what the molecules are doing. If the molecules begin sticking together, for example, the pattern begins to shift.

In the new study, the researchers created synthetic membranes that contained a small protein, called GM1, that is a primary target that cholera toxins bind with in order to get into a cell. When they mixed these membranes with cholera toxin B, they measured a binding force consistent with that obtained by other methods.

The researchers performed similar validation tests with naturally derived membranes and three membrane proteins, one associated with breast cancer, another associated with pain and inflammation and the neurotransmitter GABA known to aid in relaxation and sleep and to regulate anxiety.

When they mixed the membranes containing each of these proteins with molecules known to bind with them, the BSI technique provided measurements that agreed with the values obtained by other methods, the scientists reported.

Vanderbilt has applied for and received three patents on the process and has several other patents pending.

The university has issued an exclusive license to develop the technology to Molecular Sensing, Inc. Bornhop is one of the founders of the start-up and serves as its chief scientist.

Vanderbilt research associate Amanda Kussrow and Michael Baksh, Mauro Mileni and M.G. Finn from The Scripps Research Institute contributed to the study, which was funded by awards from the National Institutes of Health, Joint Center for Innovative Membrane Protein Technologies and the Skaggs Institute for Chemical Biology.

Story Source:

The above story is reprinted (with editorial adaptations) from materials provided by Vanderbilt University.

Journal Reference:

Michael M Baksh, Amanda K Kussrow, Mauro Mileni, M G Finn, Darryl J Bornhop. Label-free quantification of membrane-ligand interactions using backscattering interferometry. Nature Biotechnology, 2011; DOI: 10.1038/nbt.1790