Entry prohibited for AIDS viruses: Peptide triazole inhibitors disrupt cell-free HIV-1

The initial entry of HIV-1 into host cells remains a compelling yet elusive target for the development of agents to prevent infection, a critical need in the fight against the global AIDS epidemic.

A collaborative research effort led by Irwin Chaiken at Drexel University and Drexel University College of Medicine (Philadelphia, PA, USA) has demonstrated that modified peptide triazole inhibitors which specifically target the HIV-1 envelope (Env) protein gp120 can physically disrupt virus particles in the absence of host cells, and the results are reported in ChemMedChem.

The Drexel team found that under conditions similar to those at which a newly designed peptide triazole (KR13) inhibits infection of host cells by an HIV-1 pseudovirus, it also causes virus rupture and release of an internal HIV-1 protein called gag p24 when incubated with virus alone.

Both inhibition of cell infection and p24 release are enhanced substantially by the multivalent display of KR13 on gold nanoparticles.

The novel antagonist design and reported characterization data could lead to the creation of a virucide to suppress initial HIV-1 infection, viremia in infected individuals, and the spread of infection between individuals. Such agents could be used for HIV-1 microbicides and therapeutics.

These results also suggest that ligand-specific pathogen rupture may be possible for other viruses that contain metastable prefusion surface protein complexes, such as influenza, Ebola, and Dengue.

More information: Irwin Chaiken, Cell-Free HIV-1 Virucidal Action by Modified Peptide Triazole Inhibitors of Env gp120, ChemMedChem 2011, 6, No. 8, http://dx.doi.org/ … dc.201100177

Rhodium-iron catalyst helps increase yield of hydrogen gas in steam reforming of ethanol

Vehicles powered by hydrogen fuel cells generate no exhaust emissions other than clean water vapor. Unfortunately, producing and distributing large quantities of hydrogen gas is impossible with current infrastructures. Researchers are instead turning to on-board fuel processing -- using small-scale reactors to 'reform' gasoline into hydrogen with the help of high-temperature steam -- to aid implementation of this alternative technology.

Luwei Chen and co-workers at the A*STAR Institute of Chemical and Engineering Sciences and the National University of Singapore have now developed a catalyst that makes on-board hydrogen generation safer and easier to perform than ever before. By combining the beneficial properties of two metals into a nanostructured material, the catalyst can eliminate carbon monoxide (CO) emissions from the low-temperature steam reforming of ethanol—a significant advantage over current approaches.

Ethanol is an attractive fuel for on-board hydrogen generation because it can be sourced from renewable biological materials. However, the steam reforming of ethanol is a complex procedure with many possible byproducts. Some of the most serious contaminants are carbonaceous deposits, known as coke, which plug up catalysts and prevent them from working. Operation at high temperatures of 550–800 °C can mitigate coking effects, but these conditions also lead to more CO gas emissions during the reforming reactions.

The research team resolved this dilemma by combining rhodium crystals, which can catalyze ethanol steam reforming at low temperatures, with iron oxide nanoparticles onto a solid substrate. Chen explains that iron oxide catalyzes the water–gas shift reaction, an additional process that converts CO and water into hydrogen and carbon dioxide (see image). “These two components work together in the same temperature range, making them a good match,” she says.

Experiments revealed that this new substance performed admirably at temperatures of 350–400 °C, yielding about four units of hydrogen gas from every ethanol molecule, with no CO byproducts. Furthermore, the rhodium–iron oxide system had an extraordinarily long lifetime—steam reforming could proceed for over 300 hours without coke deposits deactivating the catalyst.

Additional analysis provided the researchers with a plausible mechanistic understanding of their discovery. While the strong bonding between CO and rhodium creates coke deposits, the presence of iron oxide disrupts this chemical equilibrium. CO molecules migrate from the rhodium over iron nanoparticles, where they undergo a water–gas shift reaction that enhances hydrogen output.

According to Chen, removing CO emissions from bioethanol steam reforming should lead to the design of simpler and cheaper on-board reactors, bringing these devices one step closer to widespread adoption.

More information: Chen, L. et al. Carbon monoxide-free hydrogen production via low-temperature steam reforming of ethanol over iron-promoted Rh catalyst. Journal of Catalysis 276, 197–200 (2010).

Provided by Agency for Science, Technology and Research (A*STAR)

Unique gel capsule structure enables co-delivery of different types of drugs

Researchers at the Georgia Institute of Technology have designed a multiple-compartment gel capsule that could be used to simultaneously deliver drugs of different types. The researchers used a simple "one-pot" method to prepare the hydrogel capsules, which measure less than one micron.

The capsule's structure -- hollow except for polymer chains tethered to the interior of the shell -- provides spatially-segregated compartments that make it a good candidate for multi-drug encapsulation and release strategies. The microcapsule could be used to simultaneously deliver distinct drugs by filling the core of the capsule with hydrophilic drugs and trapping hydrophobic drugs within nanoparticles assembled from the polymer chains.

"We have demonstrated that we can make a fairly complex multi-component delivery vehicle using a relatively straightforward and scalable synthesis," said L. Andrew Lyon, a professor in the School of Chemistry and Biochemistry at Georgia Tech. "Additional research will need to be conducted to determine how they would best be loaded, delivered and triggered to release the drugs."

 

Lyon and Xiaobo Hu, a former visiting scholar at Georgia Tech, created the microcapsules. As a graduate student at the Research Institute of Materials Science at the South China University of Technology, Hu is co-advised by Lyon and Zhen Tong of the South China University of Technology. Funding for this research was provided to Hu by the China Scholarship Council.

The researchers began the two-step, one-pot synthesis procedure by forming core particles from a temperature-sensitive polymer called poly(N-isopropylacrylamide). To create a dissolvable core, they formed polymer chains from the particles without a cross-linking agent. This resulted in an aggregated collection of polymer chains with temperature-dependent stability.

"The polymer comprising the core particles is known for undergoing chain transfer reactions that add cross-linking points without the presence of a cross-linking agent, so we initiated the polymerization using a redox method with ammonium persulfate and N,N,N',N'-tetramethylethylenediamine. This ensured those side chain transfer reactions did not occur, which allowed us to create a truly dissolvable core," explained Lyon.

For the second step in the procedure, Lyon and Hu added a cross-linking agent to a polymer called poly(N-isopropylmethacrylamide) to create a shell around the aggregated polymer chains. The researchers conducted this step under conditions that would allow any core-associated polymer chains that interacted with the shell during synthesis to undergo chain transfer and become grafted to the interior of the shell.

Cooling the microcapsule exploited the temperature-sensitivities of the polymers. The shell swelled with water and expanded to its stable size, while the free-floating polymer chains in the center of the capsule diffused out of the core, leaving behind an empty space. Any chains that stuck to the shell during its synthesis remained. Because the chains control the interaction between the particles they store and their surroundings, the tethered chains can act as hydrophobic drug carriers.

Compared to delivering a single drug, co-delivery of multiple drugs has several potential advantages, including synergistic effects, suppressed drug resistance and the ability to tune the relative dosage of various drugs. The future optimization of these microcapsules may allow simultaneous delivery of distinct classes of drugs for the treatment of diseases like cancer, which is often treated using combination chemotherapy.

Provided by Georgia Institute of Technology (news : web)

A flash of insight: Chemist uses lasers to see proteins at work

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Binghamton University researcher Christof Grewer thinks he has an important brain transport protein -- glutamate transporter -- figured out and he's taking aim with lasers. Credit: Jonathan Cohen

Binghamton University researcher Christof Grewer thinks he has an important brain transport protein – glutamate transporter – figured out. And he's using a novel approach to spy on them by taking aim with lasers.

Grewer, a biophysical chemist, studies glutamate transport proteins, miniscule components of our brains that move glutamate among cells. Glutamate, an important molecule in cellular metabolism, is also a neurotransmitter. He explains his research on these tiny proteins in the brain using an analogy: imagine never having seen a car before and trying to determine what makes the vehicle run.

"We would be interested in seeing what happens when the car is moving, and we'd take pictures of that," he says. "We'd see the pistons moving, and that would be the beginning of understanding."

Scientists know the transport proteins are important, and they know they move glutamate in and out of cells through a sort of door in the cell wall, known as a glutamate transporter. But exactly how the proteins trigger those doors in the cell wall, and what makes them move glutamate to the inside or outside of a cell, is unknown.

Learning how those triggers function could have major implications for human health. For example, during a stroke, when blood and oxygen to the brain are restricted, brain cells release glutamate into the space surrounding them. That starts a toxic chain that can kill brain cells and harm certain brain functions. Knowing how the glutamate molecules are transported through cell walls could one day lead to drugs that help or halt the transport.

Grewer — one of perhaps two dozen researchers in the world who work on this problem — switches analogies as he continues describing the way these proteins move.

"Think about people being transported in an elevator in a tall building," he says. "So in order for that to work, the door of the elevator has to open, and then the person has to step into the elevator. And then the elevator brings you to a higher floor, and then the door has to open, and the person has to walk out."

In this case, glutamate molecules are the people. The elevator cars are the glutamate transporters. And the electricity and wires that move elevator doors are — well, that's what he's trying to figure out. Grewer's brainstorm was to create a method that uses lasers to trigger the transports' action. By controlling when the movement happens, he can document it. It all goes back to his analogy of photographing a car's pistons. Taking snapshots may illuminate how the transporters and glutamate molecules work together.

Grewer stumbled onto the glutamate transporters. When he was a graduate student in physical chemistry at Johann Wolfgang Goethe-University in Frankfurt, Germany, his research focused on chemistry and light. His introduction to biochemistry — and to glutamate receptors — came during a post-doctoral fellowship at
Cornell University.

"We were trying to activate these receptors on a very fast time scale," he says. "It's not that easy to do."

His background in chemistry and physics brought fresh insight to the lab. What if, he thought, a flash of light could help trigger the transport process? By timing the reactions, the researchers could better capture what happens during the glutamate transfer.

"They were so interesting to me that I just had to stay with them," Grewer says of glutamate transporters. "I thought, that is just the most amazing thing to study."

Most biochemical research on the brain focuses on possible cures and many researchers are experimenting with known drugs to judge their effect on brain function.

In most proteins, and in biology, researchers know what the genetic code and the DNA look like. The number of proteins in the body is also a known factor. But what's not unclear is how these proteins function. And that's where Grewer's work comes in. He has become a pioneer in the usage of lasers, which although used on other types of proteins, has not been used before in this area of study.

Provided by Binghamton University