A surprising interaction may enable development of new HIV treatment strategies by exploiting infection with multiple pathogens.  The research, published by Cell Press in the September 11th issue of the journal Cell Host and Microbe, demonstrates that a drug commonly used to treat herpes directly suppresses HIV in coinfected tissues and thus may be beneficial for patients infected with both viruses.

Commonly, individuals infected with HIV are infected also with other microbes.  Infection with human herpesvirus (HHV), especially with herpes simplex virus-2 (HSV-2), is often associated with HIV.  These HHV infections may be either active or dormant, but HIV infection makes HHV reactivation more likely.

For many years, acyclovir (ACV), a well-studied drug, has been used safely to treat HHV in humans.  “HHV has a unique ability to phosphorylate ACV to activate it, making the drug quite specific for HHV and, for the same reason, relatively non-active against other viruses, including HIV,” offers senior study author Dr. Leonid Margolis from the National Institute of Health.  Nevertheless, some patients coinfected with HIV and HSV-2 exhibit lower HIV levels after ACV treatment.

“We decided to investigate this phenomenon experimentally using small blocks of human tissues” says Dr. Margolis.  “Drs.  Andrea Lisco and Christophe Vanpouille who performed this work in my laboratory found that although ACV doesn’t inhibit HIV in ’sterile’ cell lines, it does, surprisingly, suppress HIV in tissues that carry no HSV-2 but various other HHVs.”  In collaboration with a prominent AIDS researcher Dr. Raymond Schinazi from Emory University and Dr. Matthias Gotte from McGill University, the researchers found that phosphorylated ACV that is formed in HHV-infected cells directly inhibits the HIV-1 reverse transcriptase (RT), thus preventing HIV from copying itself.

These results not only help to explain the response to ACV seen in patients coinfected with HSV-2 and HIV, but also suggest that ACV may be used against HIV in patients infected with various other HHVs, including the low-pathogenic and ubiquitous HHV-6 and HHV-7.  Moreover, in collaboration with Drs.  Balzarini from Catholic University of Leuven and McGuigan from Cardiff University, Dr. Margolis and his team demonstrated that new strategies for development of novel HIV inhibitors based on ACV structure can now be developed.  “We provide definitive experimental evidence of inhibition of HIV-1 RT activity by phosphorylated ACV and demonstrate that ACV phosphorylation occurring in human tissues infected by various HHVs transforms this widely-used inexpensive anti-herpes drug into a direct HIV inhibitor,” concludes Dr. Margolis.

A drug used to increase blood production in both medical treatments and athletic doping scandals seems also to improve memory in those using it.  New research published in the open access journal BMC Biology shows that the memory enhancing effects of erythropoietin (EPO) are not related to its effects on blood production but due to direct influences on neurons in the brain.  The findings may prove useful in the treatment of diseases affecting brain function, such as schizophrenia, multiple sclerosis, and Alzheimer’s.

Patients given EPO to treat chronic kidney failure had been observed to have improved cognition after starting the drug.  “These effects of EPO were thought to result from the blood-boosting effects of the drug”, explains Hannelore Ehrenreich at the Max Planck Institute, “but the finding of receptors for EPO on nerve cells in the brain suggests that some other mechanism might be involved.”

To investigate the mechanisms of EPO-enhanced cognition, the researchers injected mice with EPO every other day for three weeks (11 doses) to test the effects of long-term exposure.  After the treatment period, mice given EPO had better memory in some situations than did mice that had been given a placebo instead.  The improvement in memory lasted up to three weeks from the last EPO dose and outlasted increased blood-cell production, but had disappeared by four weeks.  Mice given three doses saw no benefit with respect to memory improvement.

“Young mice systematically treated with EPO for three weeks have improved memory, similar to the dramatic improvements observed in endurance and muscular performance athletes who use EPO to boost performance”, says Ehrenreich.  The specific memory improvements were associated with the hippocampus, a structure in the brain involved in learning and memory, among other functions.

The researchers did a series of experiments on hippocampal tissue taken from the mice and found that EPO directly affected the neurons in this structure.  “EPO had pronounced effects on short-term and long-term plasticity in the hippocampus as well as on synaptic transmission”, the researchers report.  “Treatment with EPO seems to increase the number of inhibitory circuits, which actually increases the efficiency of transmission of excitatory nerve impulses in specific neurons, resulting in greater short-term and long-term plasticity in memory pathways in the hippocampus.”

These findings begin to shed light on the mechanisms of improvements in cognition seen in patients with schizophrenia and multiple sclerosis as a result of treatment with this drug.  As well as working to refine these findings, further studies might also investigate the effects of EPO on other brain regions that might be associated with improvements in motor functions in multiple sclerosis, and investigate the potential of using EPO or targeting the networks involved in EPO-generated neuronal plasticity in the treatment of neurodegenerative diseases.

Laboratories that perform pre-employment drug screening are fighting back — against hundreds of products now on the market that promise to mask evidence of illicit drug use, according to an article scheduled for the Sept. 8 issue of Chemical & Engineering News, ACS’ weekly newsmagazine.

In the article, C&EN Senior Business Editor Melody Voith points out that job applicants now have access to an array of products purported to alter urine samples to hide evidence of marijuana, cocaine, and other illegal drugs.  Some are supposed to dilute evidence of illicit drugs to levels undetectable by conventional tests.  Others used adulterants advertised to inactivate or destroy chemical markers used to identify drugs.

Drug-testers are responding with more sensitive tests that can identify tell-tale chemical signs of diluted urine samples or quickly detect the presence of adulterants.  The article also explains that testers may get a boost from proposed new drug testing guidelines from the U.S. Department of Health & Human Services.  They would permit use of hair and saliva samples in drug screening of candidates for federal jobs.  That screening could indentify illicit drugs more reliably than urine samples alone, the article notes.

Researchers in Florida are reporting an advance toward tapping the enormous potential of an emerging new group of antibiotics identical to certain germ-fighting proteins found in the human immune system.  Their study, which may help fight the growing epidemic of drug-resistant infections, is in the current (August) issue of ACS’ Biomacromolecules, a monthly journal.

In the new study, D. Matthew Eby, Glenn Johnson, and Karen Farrington point out that scientists have long eyed the germ-fighting potential of antimicrobial peptides (AMPs).  These small proteins fight a wide range of bacteria and fungi in the body and have the potential to be developed into powerful drugs to overcome infections that are resistant to conventional drugs.  But scientists report difficulty producing effective AMPs because the antibiotics are fragile and easily destroyed in the body.  An effective way to stabilize them is needed, they say.

In laboratory studies, the researchers showed that the coating protected the antibiotics from destruction by other chemicals while allowing the release of a controlled antibiotic dose for an extended period of time.  These features are key to the effective use of AMPs as antibiotics, they say.

Substances in marijuana show promise for fighting deadly drug-resistant bacterial infections, including so-called “superbugs,” without causing the drug’s mood-altering effects, scientists in Italy and the United Kingdom are reporting.  Besides serving as infection-fighting drugs, the substances also could provide a more environmentally-friendly alternative to synthetic antibacterial substances now widely used in personal care items, including soaps and cosmetics, they say.  Their study is scheduled for the Sept. 26 issue of ACS’ monthly Journal of Natural Products.

In the new study, Giovanni Appendino and colleagues point out that scientists have known for years that marijuana contains antibacterial substances.  However, little research has been done on those ingredients, including studies on their ability to fight antibiotic resistant infections, the scientists say.

To close that gap, researchers tested five major marijuana ingredients termed cannabinoids on different strains of methicillin-resistant Staphylococcus aureus (MRSA), a “superbug” increasingly resistant to antibiotics.  All five substances showed potent germ-killing activity against these drug-resistant strains, as did some synthetic non-natural cannabinoids, they say.  The scientists also showed that these substances appear to kill bacteria by different mechanisms than conventional antibiotics, making them more likely to avoid bacterial resistance, the scientists note.  At least two of the substances have no known mood-altering effects, suggesting that they could be developed into marijuana-based drugs without causing a “high.”

Scientists have gained new insight into a mechanism whereby chemotherapy may actually assist the rapid regrowth of tumors after treatment.  The research, published by Cell Press in the September issue of the journal Cancer Cell, also helps to explain why a combination of traditional chemotherapy with drugs that block formation of new blood vessels might impede the devastating tumor recovery that often follows cancer therapy.

“Chemotherapy remains the most commonly employed form of systemic cancer treatment.  However, although partial or complete shrinkage of tumor mass is frequently induced in chemotherapy-responsive tumors, survival benefits of such responses can be compromised by rapid regrowth of the drug-treated tumors,” says senior study author Dr. Robert S. Kerbel from the University of Toronto.

Clinical trials have indicated that drugs that inhibit the growth of blood vessels, called antiangiogenic drugs, can sometimes enhance the effectiveness of traditional chemotherapy.  For example, coadministration of the antiangiogenic drug bevacizumab with the chemotherapeutic agent paclitaxel improves survival benefits for metastatic breast cancer and small cell lung cancer.  In contrast, coadministration of bevacizumab with gemcitabine for treatment of pancreatic cancer does not increase the effectiveness of chemotherapy alone.

“Several hypotheses have been proposed to explain how antiangiogenic drugs enhance the treatment efficacy of cytotoxic chemotherapy, including impairing the ability of chemotherapy-responsive tumors to regrow after therapy,” says author Dr. Yuval Shaked.  Drs.  Kerbel, Shaked, and colleagues had previously shown that treatment with a type of cytotoxic-like agent known as a vascular disrupting agent (VDA) induces rapid mobilization of cells called circulating endothelial progenitors (CEPs) from the bone marrow compartment that helps the tumor to regrow blood vessels and thereby recover from treatment.

The researchers built on this earlier observation by analyzing whether different, conventional chemotherapeutic drugs had variable abilities to impact CEP mobilization and whether antiangiogenic drugs could block chemotherapy-induced CEP responses and hence amplify their effectiveness.  They found that paclitaxel rapidly induced CEP mobilization whereas gemcitabine did not.  They went on to show that pharmacological inhibition of CEP mobilization by combination treatment with an antiangiogenic drug or treatment of mutant mice deficient in CEPs resulted in enhanced antitumor effects mediated by paclitaxel but not gemcitabine.

“Our results provide a new perspective regarding the impact that conventional chemotherapy can have on tumor angiogenesis and hence how combination with antiangiogenic drugs may amplify the antitumor effects of chemotherapy,” explains Dr. Kerbel.  “Further, our findings provide a potential explanation of why not all chemotherapy drugs will necessarily have their efficacy enhanced by the addition of an antiangiogenic agent when the mechanism involves blunting CEP mobilization acutely induced by the chemotherapy drug.”

Researchers from the European Molecular Biology Laboratory (EMBL) discovered a new way to make use of drugs’ unwanted side effects.  They developed a computational method that compares how similar the side effects of different drugs are and predicts how likely the drugs act on the same target molecule.  The study, published in Science this week, hints at new uses of marketed drugs.

Similar drugs often share target proteins, modes of action and unpleasant side effects.  In reverse this means that drugs that evoke similar side effects likely act on the same molecular targets.  A team of EMBL researchers now developed a computational tool that compares side effects to test if they can predict common targets of drugs.

“Such a correlation not only reveals the molecular basis of many side effects, but also bears a powerful therapeutic potential.  It hints at new uses of marketed drugs in the treatment of diseases they were not specifically developed for,” says Peer Bork, Joint Coordinator of EMBL’s Structural and Computational Biology Unit.

The approach would prove particularly useful for chemically dissimilar drugs used in different therapeutic areas that nevertheless have an overlapping, so far unknown protein target profile.  Similar strategies have proven successful in the past.  For example, the drug marketed as Viagra was initially developed to treat angina, but its side effects of prolonged penile erection led to a change in its therapeutic area.

Applying the new method to 746 marketed drugs, the scientists found 261 dissimilar drugs that in addition to their known action also likely bind to other unexpected molecular targets.  20 of these drugs were then tested experimentally and 13 showed binding to the targets that were predicted by side effect similarity.  Testing 9 of these drugs further in cellular assays they all showed activity and thus a desired effect on the cell through their interaction with the newly discovered target proteins.

The results reveal that side effects can help find new, relevant drug-target interactions that might form the basis of new therapies.  The brain enhancer Donepezil, for example, proved to share a target with the anti-depressant Venlafaxine, supporting that Donepezil could be also used to treat depression.

The big advantage of marketed drugs is that they have already been tested and approved for safe use in patients.  This means they can move a lot faster from bench to bedside than newly discovered drugs that often take up to 15 years before they can be applied in patients.

“With some more tests and refinement our method could in future be applied on a bigger scale.  New drugs could routinely be checked in the computer for additional hidden targets and potential use in different therapeutic areas.  This will save a lot of money and would speed up drug development tremendously,” concludes Bork.

Viruses are true experts at importing genetic material into the cells of an infected organism. This trait is now being exploited for gene therapy, in which genes are brought into the cells of a patient to treat genetic diseases or genetic defects. Korean researchers have now made an artificial virus. As described in the journal Angewandte Chemie, they have been able to use it to transport both genes and drugs into the interior of cancer cells.

Natural viruses are extremely effective at transporting genes into cells for gene therapy; their disadvantage is that they can initiate an immune response or cause cancer. Artificial viruses do not have these side effects, but are not especially effective because their size and shape are very difficult to control—but crucial to their effectiveness. A research team headed by Myongsoo Lee has now developed a new strategy that allows the artificial viruses to maintain a defined form and size.

The researchers started with a ribbonlike protein structure (β-sheet) as their template. The protein ribbons organized themselves into a defined threadlike double layer that sets the shape and size. Coupled to the outside are “protein arms” that bind short RNA helices and embed them. If this RNA is made complementary to a specific gene sequence, it can very specifically block the reading of this gene. Known as small interfering RNAs (siRNA), these sequences represent a promising approach to gene therapy.

Glucose building blocks on the surfaces of the artificial viruses should improve binding of the artificial virus to the glucose transporters on the surfaces of the target cells. These transporters are present in nearly all mammalian cells. Tumor cells have an especially large number of these transporters.

Trials with a line of human cancer cells demonstrated that the artificial viruses very effectively transport an siRNA and block the target gene.

In addition, the researchers were able to attach hydrophobic (water repellant) molecules—for demonstration purposes a dye—to the artificial viruses. The dye was transported into the nuclei of tumor cells. This result is particularly interesting because the nucleus is the target for many important antitumor agents.

Magnetic nanoparticles (with a size of some few to several hundred nanometres) are a new, promising means of fighting cancer. The particles serve as a carrier for drugs: “loaded” with the drugs, the nanoparticles are released into the blood stream, where they move until they come under the influence of a targeting magnetic field which holds them on to the tumour - until the drug has released its active agent. Besides this pharmaceutical effect, also a physical action can be applied: an electromagnetic a.c. field heats up the accumulated particles so much that they destroy the tumour. Both therapeutic concepts have the advantage of largely avoiding undesired side effects on the healthy tissue.

These procedures have already been successfully been applied in the animal model and have, in part, already been tested on patients. Here it is important to know before application whether the particles tend to aggregate and thus might occlude blood vessels. Information about this can be gained by magnetorelaxometry developed at the PTB. In this procedure, the particles are shortly magnetised by a strong magnetic field in order to measure their relaxation after the switch-off of the field by means of superconducting quantum interferometers, so-called “SQUIDs”. Conclusions on their aggregation behaviour in these media can be drawn from measurements of suspensions of nanoparticles in the serum or in whole blood. As an example, it could be shown in this way that certain nanoparticles in the blood serum form clusters with a diameter of up to 200 nm - a clear indication of aggregation, so that these nanoparticles do not appear to be suitable for therapy.

At present, the high technical effort connected with the use of helium-cooled magnetic field sensors is still standing in the way of using this method routinely in practice. In a joint project with Braunschweig Technical University supported by the Ministry of Education and Research (BMBF), the procedure is currently being transferred to a simpler technology based on fluxgate magnetometers.

The results of the first orders from customers have served, for example, to optimise the paint drying process in the automobile industry, the thermal design of furnaces as well as the monitoring of glass forming processes.

Another measuring facility is currently being set up in the PTB which will allow emissivity measurements to be performed under vacuum conditions in an extended temperature and wavelength range - in particular for space applications.