Monday, March 7, 2011

Antifungal compound found on tropical seaweed has promising antimalarial properties

A group of chemical compounds used by a species of tropical seaweed to ward off fungus attacks may have promising antimalarial properties for humans. The compounds are part of a unique chemical signaling system that seaweeds use to battle enemies -- and that may provide a wealth of potential new pharmaceutical compounds.

Using a novel analytical process, researchers at the Georgia Institute of Technology found that the complex antifungal molecules are not distributed evenly across the seaweed surfaces, but instead appear to be concentrated at specific locations -- possibly where an injury increases the risk of fungal infection.

A Georgia Tech scientist reports on the class of compounds, known as bromophycolides, at the annual meeting of the American Association for the Advancement of Science (AAAS) Feb. 21, 2011 in Washington, D.C. The research, supported by the National Institutes of Health, is part of a long-term study of chemical signaling among organisms that are part of coral reef communities.

"The language of chemistry in the natural world has been around for billions of years, and it is crucial for the survival of these species," said Julia Kubanek, an associate professor in Georgia Tech's School of Biology and School of Chemistry and Biochemistry. "We can co-opt these chemical processes for human benefit in the form of new treatments for diseases that affect us."

More than a million people die each year from malaria, which is caused by the parasite Plasmodium falciparum. The parasite has developed resistance to many antimalarial drugs and has begun to show resistance to artemisinin -- today's most important antimalarial drug. The stakes are high because half of the world's population is at risk for the disease.

"These molecules are promising leads for the treatment of malaria, and they operate through an interesting mechanism that we are studying," Kubanek explained. "There are only a couple of drugs left that are effective against malaria in all areas of the world, so we are hopeful that these molecules will continue to show promise as we develop them further as pharmaceutical leads."

In laboratory studies led by Georgia Tech student Paige Stout from Kubanek's lab -- and in collaboration with California scientists -- the lead molecule has shown promising activity against malaria, and the next step will be to test it in a mouse model of the disease. As with other potential drug compounds, however, the likelihood that this molecule will have just the right chemistry to be useful in humans is relatively small.

Other Georgia Tech researchers have begun research on synthesizing the compound in the laboratory. Beyond producing quantities sufficient for testing, laboratory synthesis may be able to modify the compound to improve its activity -- or to lessen any side effects. Ultimately, yeast or another microorganism may be able to be modified genetically to grow large amounts of bromophycolide.

The researchers found the antifungal compounds associated with light-colored patches on the surface of the Callophycus serratus seaweed using a new analytical technique known as desorption electrospray ionization mass spectrometry (DESI-MS). The technique was developed in the laboratory of Facundo Fernandez, an associate professor in Georgia Tech's School of Chemistry and Biochemistry. DESI-MS allowed researchers for the first time to study the unique chemical activity taking place on the surfaces of the seaweeds.

As part of the project, Georgia Tech scientists have been cataloging and analyzing natural compounds from more than 800 species found in the waters surrounding the Fiji Islands. They were interested in Callophycus serratus because it seemed particularly adept at fighting off microbial infections.

Using the DESI-MS technique, researchers Leonard Nyadong and Asiri Galhena analyzed samples of the seaweed and found groups of potent antifungal compounds. In laboratory testing, graduate student Amy Lane found that these bromophycolide compounds effectively inhibited the growth of Lindra thalassiae, a common marine fungus.

"The alga is marshalling its defenses and displaying them in a way that blocks the entry points for microbes that might invade and cause disease," Kubanek said. "Seaweeds don't have immune responses like humans do. But instead, they have some chemical compounds in their tissues to protect them."

Though all the seaweed they studied was from a single species, the researchers were surprised to find two distinct groups of antifungal chemicals. From one seaweed subpopulation, dubbed the "bushy" type for its appearance, 23 different antifungal compounds were identified. In a second group of seaweed, the researchers found 10 different antifungal compounds -- all different from the ones seen in the first group.

In the DESI-MS technique, a charged stream of polar solvent is directed at the surface of a sample under study at ambient pressure and temperature. The spray desorbs molecules, which are then ionized and delivered to the mass spectrometer for analysis.

"Our collaborative team of researchers from the Department of Biomedical Engineering and the College of Sciences has worked within the Bioimaging Mass Spectrometry Center at Georgia Tech to better understand the mechanisms of chemical defenses in marine organisms," said Fernandez. "This is an example of cross-cutting interdisciplinary research that characterizes our institute."

Kubanek is hopeful that other useful compounds will emerge from the study of signaling compounds in the coral reef community.

"In the natural world, we have seaweed that is making these molecules and we have fungi that are trying to colonize, infect and perhaps use the seaweed as a substrate for its own growth," Kubanek said. "The seaweed uses these molecules to try to prevent the fungus from doing this, so there is an interaction between the seaweed and the fungus. These molecules function like words in a language, communicating between the seaweed and the fungus."

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Georgia Institute of Technology Research News, via EurekAlert!, a service of AAAS.

Breakthrough in molecular motors: First molecular piston capable of self-assembly

Researchers from CNRS and the Université de Bordeaux, in collaboration with a Chinese team (1), have developed the first molecular piston capable of self-assembly. Their research represents a significant technological advance in the design of molecular motors. Such pistons could, for example, be used to manufacture artificial muscles or create polymers with controllable stiffness.

The results are published on 4 March 2011 in the journal Science.

Living organisms make extensive use of molecular motors in fulfilling some of their vital functions, such as storing energy, enabling cell transport or even moving about in the case of bacteria. Since the molecular layouts of such motors are extremely complex, scientists seek to create their own, simpler versions. The motor developed by the international team headed by Ivan Huc (2), CNRS researcher in the "Chimie et Biologie des Membranes et des Nanoobjets" Unit (CNRS/Université de Bordeaux), is a "molecular piston." Like a real piston, it comprises a rod on which a moving part slides, except that the rod and the moving part are only several nanometers long.

More specifically, the rod is formed of a slender molecule, whereas the moving part is a helix-shaped molecule (both are derivatives of organic compounds especially synthesized for the purpose). How can the helicoidal molecule move along the rod? The acidity of the medium in which the molecular motor is immersed controls the progress of the helix along the rod: by increasing the acidity, the helix is drawn towards one end of the rod, as it then has an affinity for that portion of the slender molecule. By reducing the acidity, the process is reversed and the helix goes in the other direction.

This device has a crucial advantage compared to existing molecular pistons: self-assembly. In previous versions, which take the form of a ring sliding along a rod, the moving part is mechanically passed onto the rod with extreme difficulty. Conversely, the new piston is self-constructing: the researchers designed the helicoidal molecule specifically so that it winds itself spontaneously around the rod, while retaining enough flexibility for its lateral movements.

By allowing the large scale manufacturing of such molecular pistons, this self-assembly capacity augurs well for the rapid development of applications in various disciplines: biophysics, electronics, chemistry, etc. By grafting several pistons together end-to-end, it could be possible, for example, to produce a simplified version of an artificial muscle, capable of contracting on demand. A surface bristling with molecular pistons could, as and when required, become an electrical conductor or insulator. Finally, a large-scale version of the rod on which several helices could slide would provide a polymer of adjustable mechanical stiffness. This goes to show that the possibilities for this new molecular piston are (almost) infinite.

(1) From the Beijing National Laboratory for Molecular Sciences

(2) His team is part of the Institut Européen de Chimie et Biologie.

Story Source:

The above story is reprinted (with editorial adaptations) from materials provided by CNRS (Délégation Paris Michel-Ange).

Journal Reference:

Quan Gan, Yann Ferrand, Chunyan Bao, Brice Kauffmann, Axelle Grélard, Hua Jiang, Ivan Huc. Helix-Rod Host-Guest Complexes with Shuttling Rates Much Faster than Disassembly. Science, 4 March 2011; Vol. 331 no. 6021 pp. 1172-1175 DOI: 10.1126/science.1200143

Scientists create cell assembly line: New technology synthesizes cellular structures from simple starting materials

 Borrowing a page from modern manufacturing, scientists from the Florida campus of The Scripps Research Institute have built a microscopic assembly line that mass produces synthetic cell-like compartments.

The new computer-controlled system represents a technological leap forward in the race to create the complex membrane structures of biological cells from simple chemical starting materials.

"Biology is full of synthetic targets that have inspired chemists for more than a century," said Brian Paegel, Scripps Research assistant professor and lead author of a new study published in the Journal of the American Chemical Society. "The lipid membrane assemblies of cells and their organelles pose a daunting challenge to the chemist who wants to synthesize these structures with the same rational approaches used in the preparation of small molecules."

While most cellular components such as genes or proteins are easily prepared in the laboratory, little has been done to develop a method of synthesizing cell membranes in a uniform, automated way. Current approaches are capricious in nature, yielding complex mixtures of products and inefficient cargo loading into the resultant cell-like structures.

The new technology transforms the previously difficult synthesis of cell membranes into a controlled process, customizable over a range of cell sizes, and highly efficient in terms of cargo encapsulation.

The membrane that surrounds all cells, organelles and vesicles -- small subcellular compartments -- consists of a phospholipid bilayer that serves as a barrier, separating an internal space from the external medium.

The new process creates a laboratory version of this bilayer that is formed into small, cell-sized compartments.

How It Works

"The assembly-line process is simple and, from a chemistry standpoint, mechanistically clear," said Sandro Matosevic, research associate and co-author of the study.

A microfluidic circuit generates water droplets in lipid-containing oil. The lipid-coated droplets travel down one branch of a Y-shaped circuit and merge with a second water stream at the Y-junction. The combined flows of droplets in oil and water travel in parallel streams toward a triangular guidepost.

Then, the triangular guide diverts the lipid-coated droplets into the parallel water stream as a wing dam might divert a line of small boats into another part of a river. As the droplets cross the oil-water interface, a second layer of lipids deposits on the droplet, forming a bilayer.

The end result is a continuous stream of uniformly shaped cell-like compartments.

The newly created vesicles range from 20 to 70 micrometers in diameter -- from about the size of a skin cell to that of a human hair. The entire circuit fits on a glass chip roughly the size of a poker chip.

The researchers also tested the synthetic bilayers for their ability to house a prototypical membrane protein. The proteins correctly inserted into the synthetic membrane, proving that they resemble membranes found in biological cells.

"Membranes and compartmentalization are ubiquitous themes in biology," noted Paegel. "We are constructing these synthetic systems to understand why compartmentalized chemistry is a hallmark of life, and how it might be leveraged in therapeutic delivery."

Story Source:

The above story is reprinted (with editorial adaptations  from materials provided by Scripps Research Institute, via EurekAlert!, a service of AAAS.

Journal Reference:

Sandro Matosevic, Brian M. Paegel. Stepwise Synthesis of Giant Unilamellar Vesicles on a Microfluidic Assembly Line. Journal of the American Chemical Society, 2011; 110210133308021 DOI: 10.1021/ja109137s

A loose grip provides better chemotherapy

Researchers at Case Western Reserve University have developed a little bomb that promises a big bang for cancer patients.

Preliminary tests show an anti-cancer drug loosely attached to gold nanoparticles starts accumulating deep inside tumors within minutes of injection and can be activated for an effective treatment within two hours. The same drug injected alone takes two days to gather and attacks the tumor from the surface -- a far less effective route.

The work, titled "Deep Penetration of a PDT Drug into Tumors by Noncovalent Drug-Gold Nanoparticle Conjugates," is published February 4 in the online edition of the Journal of the American Chemical Society.

Speeding anti-cancer drugs directly into tumors enables patients to receive lower doses of the toxic chemicals, thereby saving healthy tissue from damage and other harsh side effects suffered in traditional chemotherapy.

"We hope to lower the dosage by at least a factor of 10," said Clemens Burda, a professor of chemistry at Case Western Reserve and the senior author of the paper.

The key to success? The scientists tied an anti-cancer drug to golden missiles using a weak chemical interaction called a noncovalent bond. In molecule construction, a covalent bond is a heavy rope lashed and knotted; a noncovalent bond is a shoestring tied in a bow.

"Very often, additions to chemical systems change properties of the components of the system," Burda said. Attempts by his and other research groups to use covalent bonds for drug delivery have resulted in such complications and less than hoped-for results.

The researchers, who come from a breadth of disciplines, found that by using a noncovalent bond to attach the drug to coated gold, they eliminated interference among the desired properties of each component.

Burda's group sought to simplify the process by using materials that have well-known properties.

Gold nanoparticles have large surface areas that permit packing a lot in a tiny space. The element is inert inside the body and at less than 5 nanometers across, or less than 1/10,000 the width of a human hair, the particles quickly flow out of the blood stream and across cancer cell membranes to accumulate inside tumors.

A coat of polyethylene glycol links tightly to the gold while providing cargo space to attach other materials.

The coated gold provides an environment to physically prevent activation of the photodynamic therapy drug silicon phthalocyanine, preventing unintended toxic exposures to healthy tissues.

The loosely-held drug is released from the nanoparticle through the attraction of the drug to the lipid membrane of cancer cells. Laser light switches on the freed silicon phthalocyanine, which breaks down and kills cancer cells, shrinking the tumor.

After delivering the drug, the nanoparticles pass through the kidneys and clear the body within a week.

Burda teamed with Yu Cheng, Joseph D. Meyers, Ann-Marie Broome, Malcolm E. Kenney and James Basilion, all of Case Western Reserve.

Their work received a $1.2 million grant from the National Institutes of Health late this fall, to continue development.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Case Western Reserve University, via EurekAlert!, a service of AAAS.

Journal Reference:

Yu Cheng, Joseph D. Meyers, Ann-Marie Broome, Malcolm E. Kenney, James P. Basilion, Clemens Burda. Deep Penetration of a PDT Drug into Tumors by Noncovalent Drug-Gold Nanoparticle Conjugates. Journal of the American Chemical Society, 2011; : 110204112210047 DOI: 10.1021/ja108846h

Solving the riddle of nature’s perfect spring

 Scientists have unravelled the shape of the protein that gives human tissues their elastic properties in what could lead to the development of new synthetic elastic polymers.

University of Manchester researchers, working with colleagues in Australia and the United States, used state-of-the-art techniques to reveal the structure of tropoelastin, the main component of elastin.

Elastin allows tissues in humans and other mammals to stretch, for example when the lungs expand and contract for respiration or when arteries widen and narrow over the course of a billion heart beats.

The study, published in the Proceedings of the National Academy of Sciences, revealed how evolution has triumphed where engineering has so far failed by generating a molecule with near-perfect elasticity that will last a lifetime.

"All mammals rely on elastin to provide their tissues with the ability to stretch and then return to their original shape," said researcher Dr Clair Baldock, from the University of Manchester's Wellcome Trust Centre for Cell Matrix Research. "This high level of physical performance demanded of elastin vastly exceeds and indeed outlasts all human-made elastics.

"It is the co-ordinated assembly of many tropoelastins into elastin that gives tissues their stretchy properties and this exquisite assembly helps to generate elastic tissues as diverse as artery, lung and skin.

"We discovered that tropoelastin is a curved, spring-like molecule with a 'foot' region to facilitate attachment to cells. Stretching and relaxing experiments showed that the molecule had the extraordinary capacity to extend to eight-times its initial length and can then return to its original shape with no loss of energy, making it a near-perfect spring."

She added: "Elastics are used in applications as diverse as clothing, vehicles, tissue engineering and even space travel, so understanding how the structure of tropoelastin creates its exceptional elastic properties will hopefully enable the development of synthetic 'elastin-like' polymers with potentially wide-ranging applications and benefits."

Initiator and research project leader Tony Weiss, Professor in the School of Molecular Bioscience, The University of Sydney, added: "Tropoelastin is a tiny protein 'nanospring' in the human body. Our bodies assemble these nanosprings to put elasticity into tissues like skin, blood vessels and lung.

"Our finding is the result of more than a decade of international collaboration. Our scientific teamwork spans Australia, the UK, USA and Europe. Tropoelastin's extraordinary capacity to extend to eight-times its initial length and then return to its original shape, with no loss of energy, is nature showing us how to make an ideal nanospring."

Story Source:

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

Journal Reference:

Clair Baldock, Andres F. Oberhauser, Liang Ma, Donna Lammie, Veronique Siegler, Suzanne M. Mithieux, Yidong Tu, John Yuen Ho Chow, Farhana Suleman, Marc Malfois, Sarah Rogers, Liang Guo, Thomas C. Irving, Tim J. Wess and Anthony S. Weiss. Shape of tropoelastin, the highly extensible protein that controls human tissue elasticity. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1014280108