Novel Approach Garners Rabies Targets

Researchers from Prosetta Antivirals Inc. have used a novel approach to identify possible host proteins that could be targeted to develop anti-rabies medications. Rabies is an almost invariably fatal illness with no effective treatment, and the rabies vaccine is a postexposure prophylaxis vaccine that needs to be given within strict time limits. The authors looked for host proteins that are important for the assembly of the viral capsid, or protein shell. Such assembly was thought to be a spontaneous process, but the authors believed, based on recent studies on other viruses, that there might be host protein assemblies involved. They identified such assemblies by using cell-free protein synthesis to identify pathways critical for capsid assembly, and then identified specific proteins within those pathways. The team was able to identify both target proteins and potential inhibitors for them. They concluded that beyond the specific rabies drug candidates they identified, their studies "suggest the existence of labile assembly machines that can be rendered accessible as next-generation drug targets" by their methods. Their work appeared in the Feb. 11, 2013, advance online edition of the Proceedings of the National Academy of Sciences.

Canker Sore Drug Induces Weight Loss in Mice

Researchers from the University of Michigan have discovered that Aphthasol (amlexanox, Access Pharmaceuticals Inc.), which is approved for the treatment of canker sores and ulcers, may be useful as an anti-obesity treatment. Aphthasol inhibits two kinases, IKK-epsilon and TANK-binding kinase 1, that are induced by a high-fat diet and set off the process of inflammation once they are active. The authors reported that when they treated mice on a high-fat diet with the drug, it prevented weight gain despite the fact that it did not reduce food intake. In obese mice, the compound improved insulin sensitivity, reversed some symptoms of fatty liver, and reduced inflammation and increased heat generation in fat cells. The authors said that given these effects, and its clinical safety record, "amlexanox may be an interesting candidate for clinical evaluation in the treatment of obesity and related disorders." Their findings appeared in the Feb. 10, 2013, issue of Nature Medicine.

Blocking Endoglin: It's Complicated

Researchers from the Karolinska Institutet have found that blood vessels lacking endoglin differ from their normal counterparts in both positive and negative ways as far as the spread of cancer is concerned. Endoglin is a membrane protein that is a co-receptor for the proinflammatory cytokine TGF-beta, and the authors originally tested whether knocking out the protein might block blood vessel growth. It turned out, however, that the vessels of mice with cancer were able to adapt to the lack of endoglin and continue to produce blood vessels. Those blood vessels, moreover, had changes in their structure that made it easier for tumor cells to breach them, and mice lacking endoglin had increased metastasis. However, such animals also took longer to develop resistance to VEGF blocking anti-angiogenesis drugs, "illustrating," the authors concluded, "the therapeutic utility of combinatorial targeting of multiple angiogenic pathways for the treatment of cancer." Their work appeared in the Feb. 11, 2013, online edition of the Journal of Experimental Medicine.

New Hand Form Grabs Calcium, With Delay

By engineering a member of the so-called EF-hand protein family, researchers from the University of Minnesota have managed to make a protein that binds calcium with a delay – which resulted, they wrote, in "favorable properties for promoting cardiac relaxation." EF-hand proteins are calcium-binding proteins, but the newly engineered form has a higher-than normal affinity for magnesium and a lower one for calcium. This resulted in a protein that buffered calcium during the diastolic phase of the heartbeat. In dog and rabbit models of diastolic dysfunction, the engineered protein reversed cell deficits and corrected abnormal heart relaxation. The authors concluded that "strategic design of new EF-hand motif domains to modulate intracellular [calcium] signaling could benefit many biological systems with abnormal [calcium] handling, including the diseased heart." They published their findings in the Feb. 10, 2013, issue of Nature Medicine.

How to Stuff the Viral Envelope

Researchers at Case Western Reserve University School of Medicine have discovered the mechanism by which HIV limits itself to two RNA copies per virus particle during replication – a discovery that may allow the construction of gene therapy viral vectors that have no such limitation, allowing for better gene delivery. Basing viral vectors on lentiviruses such as HIV is promising for gene therapy from a safety perspective, but getting them to deliver enough of a therapeutic gene to have an effect has been more challenging. In their experiments, the authors showed that when HIV puts together new viral particles, those particles need a sequence piece they termed the genomic RNA packaging enhancer. HIV missing this enhancer was 50 times less infective than normal HIV. This piece of HIV is not part of current lentiviral vectors, and including it in the viral vector design has the potential for delivering therapeutic genes more efficiently. The findings appeared in the Feb. 15, 2012, issue of Cell Host & Microbe.

Yondelis Takes out Macrophages

"Tumor associated macrophages," scientists from the Italian IRCCS Clinical and Research Institute Humanitas and the Mario Negri Institute for Pharmacological Research wrote, "elicit cancer-promoting inflammation and have been implicated in cancer progression and resistance to therapies, thus representing attractive therapeutic targets." And it appears that those targets are already being attacked by an approved cancer drug: Yondelis (trabectedin, Pharmamar SA). The authors showed that trabectedin selectively induces apoptosis in monocytes and macrophages, including tumor-associated macrophages. Both mouse models and patients that were receiving trabectedin as monotherapy showed a reduction in monocytes and macrophages, but no changes in the amounts of other types of blood cells. The authors said their findings "shed unexpected light on the mode of action of a clinically useful anticancer agent, provide strong proof-of-concept evidence for macrophage targeting in humans, and open interesting perspectives for the rational exploitation of this peculiar property in therapeutic settings." Their studies were published in the Feb. 11, 2013, issue of Cancer Cell.

Receptor Circuit Plays Role in Alcohol Dependence

Researchers at the German University of Mannheim have identified a receptor, and its functioning within a specific brain circuit, whose function becomes impaired as rats are repeatedly exposed to alcohol. The authors used transcriptome analysis to show that as rats became alcohol dependent through intermittent administration of alcohol, their levels of type 2 metabotropic glutamate receptors in pyramidal cells of the infralimbic cortex declined. As rats become alcohol dependent they become willing to work harder for alcohol, and restoring glutamate receptors to their brains via gene transfer could reverse this effect. The authors autopsied the brains of alcoholics and found that they, too, had low levels of the same type of receptor in the equivalent brain area. "Normalization of mGluR2 function within this brain circuit," the authors concluded, "may be of therapeutic value." Their work appeared in the Feb. 13, 2013, issue of the Journal of Neuroscience.

Bacterial Viagra Extends Roundworm Lifespan

Researchers at New York University have shown that the roundworm C. elegans uses the nitric oxide produced by bacteria it feeds on to extend its lifespan. Nitric oxide is most famous in the general population as the signaling molecule whose function is enhanced by Viagra, but it plays important roles far beyond erections. C. elegans, unlike most other species, does not have an enzyme to make nitric oxide, and so the authors tested whether it uses the nitric oxide from the bacteria it feeds on. They found that when they knocked out nitric oxide synthase in bacteria they fed to C. elegans, the worms' lifespan was reduced by around 15 percent. They found that bacterial nitric oxide was generated inside the worms, and that it acted on the transcription factors hsf-1 and daf-16, which are known to affect stress and life expectancy. The work "provides an example of interspecies signaling by a small molecule and illustrates the lifelong value of commensal bacteria to their host." It appeared in the Feb. 15, 2013, issue of Cell.

Novel Coronavirus May Spread from Person to Person

The World Health Organization announced two cases of Novel Coronavirus (NCoV) infection in Great Britain last week. The second case, announced on Feb. 13, is a relative of the first case, announced on Feb. 11. Novel Coronavirus was first identified in April 2012. Although at 12 total, the number of confirmed cases has been minute, its fatality rate of nearly 50 percent and the fact that the SARS coronavirus very rapidly became a pandemic, if ultimately a contained one, in 2002 and 2003 have prompted the WHO to keep a careful watch on the virus. The fact that two family members – one of them without a recent travel history – have been infected is "suggestive" of person to person transmission, the WHO said in its announcement, but also noted that the risk of such transmission appears to be much lower than it was for the SARS coronavirus.

Heart Disease Risk Gene Mechanism Elucidated

Scientists at the British Queen Mary University have identified the mechanism underlying a risk variant for coronary artery disease. A number of such gene variants have been identified, but in most cases, how they affect risk has remained mysterious. The authors took a closer look at one such risk variant, within the gene ADAMTS7, which makes an enzyme – also called ADAMTS7. They found that this enzyme affects the breakdown of the structural protein thrombospondin-5, which affects how easily plaques can grow within arteries. Their work appeared in the Feb. 14, 2013, online edition of the American Journal of Human Genetics.

– Anette Breindl, Science Editor

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