A Powerful HIV inhibitor

In a significant step toward reducing the threat of HIV, UC Merced Professor Patricia LiWang has designed what may be the most effective chemical inhibitor against infection of the virus.
"We need a fairly wide arsenal of HIV drugs because the virus is always mutating," LiWang said. "Drugs become less effective as time goes on."
LiWang's inhibitor, a novel combination of two existing drugs, has a strength that ranges from several times better than existing inhibitors to several hundred times better, depending on the strain of HIV. The inhibitor works by blocking HIV from entering a person's cell at two different steps of viral entry. This so-called "entry inhibition" is at the forefront of new strategies for stopping the virus. Other existing inhibitors have different strategies, such as preventing HIV from carrying out activities like replicating or integrating into the human genome.
There are hundreds of different strains of HIV, LiWang said, and the virus mutates when it gets inside a person's body.
"However, since this drug is a combination of two inhibitors, it would be nearly impossible for a virus to mutate so it wouldn't get hit with either one of these drugs," she explained.
The research is an example of UC Merced's faculty addressing real-world health problems.
The inhibitor is a special protein produced from harmless bacteria, which allows for large amounts to be made. The inhibitor could be added to a vaginal cream that woman could apply to guard against the virus.While condoms protect against HIV, many men in sub-Saharan Africa and other areas won't wear them, and women often don't have a choice in the decision.
LiWang's findings were published in August in The Journal of Biological Chemistry. Graduate Student Bo Zhao was the first author on the paper. Marie K. Mankowski, Beth A. Snyder and Roger G. Ptakfrom the Southern Research Institute were also part of the study.
Though the discovery is promising, much more testing and development is needed before it could be used by people in countries ravaged by the AIDS epidemic. The next step would be to see if it causes inflammation or any side effects. Clinical trials would be years off.
"We hope that a company is interested in it and we hope to get funding to keep developing it and see why it works," LiWang said.

Source:MedicalNewsToday

One Drug, Many Targets: Is This The Future?

Potential molecular targets of the anti-HIV drug nelfinavir have been identified, and may explain why the drug is also effective as a cancer therapy. Findings will be published in the open-access journal PLoS Computational Biology on 28th April 2011.
Nelfinavir is a protease inhibitor that prevents replication of the HIV virus. It has also been found to have a positive effect on a number of solid tumor types but the mechanism of how the drug worked in humans was unclear. Researchers from the University of California San Diego and the City University of New York (CUNY) combined a wide array of computational techniques to investigate the molecular mechanisms underlying nelfinavir's observed anti-cancer effect and found that there are weak interactions with a multitude of molecular targets, rather than a strong interaction with a single target.
While drug molecules are designed to bind to targeted proteins in order to achieve a therapeutic effect, small drug molecules can also attach to off-target proteins with similar binding sites. The result may be unwanted side effects or, as in the case of nelfinavir, a secondary and positive effect. Philip E. Bourne, professor of pharmacology at UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences, and his colleagues suggest that it is the collective effect of these weak interactions that leads to the clinical efficacy of nelfinavir.
The computational methods used by the researchers are a useful way of searching for potential drug targets: "Computer analysis allows us to search for other binding sites that match a particular drug-binding site - like looking for other locks that can be opened by the same key," said Lei Xie, associate professor at Hunter College, CUNY. However, it is a particularly complex route to validation of drug targets. Prof. Bourne adds "This is indeed challenging, but it is hard not to believe that this broad-based systems approach represents the future of drug discovery, at least as far as small-molecule drugs are concerned."
Funding: NIH, GM078596. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


Source:Medicalnewstoday

Bodyguard for the brain

Humans are getting older and older, and the number of people with dementia is increasing. The factors controlling degeneration of the brain are still mostly unknown. However, researchers assume that factors such as stress, accumulation of toxic waste products as well as inflammation accelerate aging. But, vice versa, there are also mechanisms that can - like a bodyguard - protect the brain from degenerating, or repair defective structures.


Researchers from the Universities of Bonn and Mainz have now discovered a hitherto unknown function of the cannabinoid-1 receptor (CB1). A receptor is a protein that can bind to other substances, triggering a chain of signals. Cannabinoids such as THC – the active agent in cannabis sativa – and endocannabinoids formed by the body bind to the CB1 receptors. The existence of this receptor is also the reason for the intoxicating effect of hashish and marijuana.


Not only does the CB1 receptor have an addictive potential, but it also plays a role in the degeneration of the brain. "If we switch off the receptor using gene technology, mouse brains age much faster," said Önder Albayram, principal author of the publication and a doctoral student on the team of Professor Dr. Andreas Zimmer from the Institut für Molekulare Psychiatrie at the University of Bonn. "This means that the CB1 signal system has a protective effect for nerve cells."


Mice prove their brain power in a pool


The researchers studied mice in different age categories – young six week old animals, middle-aged ones at five months, and those of an advanced age at 12 months. The animals had to master various tasks – first, they had to find a submerged platform in the pool. Once the mice knew its location, the platform was moved, and the animals had to find it again. This was how the researchers tested how well the rodents learned and remembered.


The animals in which the CB1 receptor had been switched off (the knock-out mice) clearly differed from their kind. "The knock-out mice showed clearly diminished learning and memory capacity," said Privatdozent Dr. Andras Bilkei-Gorzo from Professor Zimmer's team, who led the study. So, animals that did not have the receptor were less successful in their search for the platform. "In addition, they showed a clear loss of nerve cells in the hippocampus," he explained further. This part of the brain is the central area for forming and storing information. In addition, the researchers found inflammation processes in the brain. As the mice advanced in age, the degenerative processes became increasingly noticeable.


Amazing parallels with the human brain


The animals with the intact CB1 receptor, to the contrary, did clearly better with regard to their learning and memory capabilities, as well as the health of their nerve cells. "The root cause of aging is one of the secrets of life," commented Albayram. This study has begun to open the door to solving this enigma. The processes in the mouse brains have a surprising number of parallels with age-related changes in human brains. So, the endocannabinoid system may also present a protective mechanism in the aging of the human brain.


The principal author cautioned, "This will require additional research." The scientists would like to better understand the mechanism by which CB1 receptors protect the brain from inflammation processes. And based on these signal chains, it might then be possible to develop substances for new therapies.


Source : University of Bonn

Genome code cracked for most common form of pediatric brain cancer

Scientists at the Johns Hopkins Kimmel Cancer Center have deciphered the genetic code for medulloblastoma, the most common pediatric brain cancer and a leading killer of children with cancer. The genetic "map" is believed to be the first reported of a pediatric cancer genome and is published online in the December 16 issue of Science Express.


Notably, the findings show that children with medulloblastoma have five- to tenfold fewer cancer-linked alterations in their genomes compared with their adult counterparts, the scientists say.


"These analyses clearly show that genetic changes in pediatric cancers are remarkably different from adult tumors. With fewer alterations, the hope is that it may be easier to use the information to develop new therapies for them," says Victor Velculescu, M.D., Ph.D., associate professor of oncology at the Johns Hopkins Kimmel Cancer Center.


"We now know what many pieces of the medulloblastoma puzzle are," adds Bert Vogelstein, M.D., Clayton Professor of Oncology and co-director of the Ludwig Center at Johns Hopkins. "Now, we must figure out how to put the puzzle together and zero in on parts of the puzzle to develop new therapies. This is what scientists will be focused on for the next decade."


The Johns Hopkins team used automated tools to sequence hundreds of millions of individual chemicals called nucleotides, which pair together in a preprogrammed fashion to build DNA and, in turn, a genome. Combinations of these nucleotide letters form genes, which provide instructions that guide cell activity. Alterations in the nucleotides, called mutations, can create coding errors that transform a normal cell into a cancerous one. The scientists at Johns Hopkins have previously mapped genome sequences for pancreatic, adult brain, breast and colon cancers with similar methods.


For the study, scientists sequenced nearly all protein-encoding genes in 22 samples of pediatric medulloblastoma and compared these sequences with normal DNA from each patient to identify tumor-specific changes or mutations. Each tumor sample had an average of 11 mutations. There were 225 mutations in all.


Then, the investigators searched through a second set of 66 medulloblastomas, including some samples from adults, to find how these mutations altered the proteins made by the genes.


The team found that most of the mutations congregate within a few gene families or pathways. The most prevalent pathway ordered the way long strands of DNA, that make up chromosomes, are twisted and shaped into dense packets that open and close depending on when genes need to be activated. Such a process is regulated by chemicals that operate outside of genes, termed "epigenetic" by scientists.


Within the epigenetic pathway, two commonly mutated genes were both involved in how molecules called histones wrap around DNA.


"These epigenetic changes may be more important than we thought in childhood cancers," says Will Parsons, M.D., Ph.D., formerly of Johns Hopkins and now an assistant professor at Texas Children's Cancer Center and Baylor College of Medicine.


Mutations in MLL2 and MLL3 were identified in 16 percent of the entire set of 88 medulloblastoma samples. Add to this three other epigenetic alterations found by the scientists in the genome scan, and the total set accounts for 20 percent of mutations in all the brain cancer samples.


Second to epigenetic pathways were gene mutations in pathways such as Hedgehog and Wnt that control tissue and organ development in humans and other animals. Both pathways have previously been linked to childhood medulloblastoma.


Cancer is the leading cause of death by disease in children in the U.S., and more children die of brain tumors than any other type of cancer. Medulloblastoma is the most common malignant brain tumor in children, occurring in about 400 children per year in the U.S.


"It's a particular challenge to treat children with brain cancer," says Parsons, "because our most effective treatments, surgery and radiation therapy, can cause significant side effects, including cognitive disabilities and hormone abnormalities. For our youngest patients, the effects can be potentially devastating."


Yet, Parsons is encouraged by the study's findings. "As oncologists, we're working to understand how specific genetic changes found in patients' cancers should guide their treatment. Any information that allows us to understand a patient's prognosis or provides clues about therapies that might work best in a patient is crucial and will help us provide better care."


Source : Johns Hopkins Medical Institutions