Posts tagged drug development
Articles and news from the latest research reports.
Green tea and red wine extracts interrupt Alzheimer’s disease pathway in cells
Natural chemicals found in green tea and red wine may disrupt a key step of the Alzheimer’s disease pathway, according to new research from the University of Leeds.
In early-stage laboratory experiments, the researchers identified the process which allows harmful clumps of protein to latch on to brain cells, causing them to die. They were able to interrupt this pathway using the purified extracts of EGCG from green tea and resveratrol from red wine.
The findings, published in the Journal of Biological Chemistry, offer potential new targets for developing drugs to treat Alzheimer’s disease, which affects some 800,000 people in the UK alone, and for which there is currently no cure.
"This is an important step in increasing our understanding of the cause and progression of Alzheimer’s disease," says lead researcher Professor Nigel Hooper of the University’s Faculty of Biological Sciences. "It’s a misconception that Alzheimer’s is a natural part of ageing; it’s a disease that we believe can ultimately be cured through finding new opportunities for drug targets like this."
Alzheimer’s disease is characterised by a distinct build-up of amyloid protein in the brain, which clumps together to form toxic, sticky balls of varying shapes. These amyloid balls latch on to the surface of nerve cells in the brain by attaching to proteins on the cell surface called prions, causing the nerve cells to malfunction and eventually die.
"We wanted to investigate whether the precise shape of the amyloid balls is essential for them to attach to the prion receptors, like the way a baseball fits snugly into its glove," says co-author Dr Jo Rushworth. "And if so, we wanted to see if we could prevent the amyloid balls binding to prion by altering their shape, as this would stop the cells from dying."
The team formed amyloid balls in a test tube and added them to human and animal brain cells. Professor Hooper said: “When we added the extracts from red wine and green tea, which recent research has shown to re-shape amyloid proteins, the amyloid balls no longer harmed the nerve cells. We saw that this was because their shape was distorted, so they could no longer bind to prion and disrupt cell function.
"We also showed, for the first time, that when amyloid balls stick to prion, it triggers the production of even more amyloid, in a deadly vicious cycle," he added.
Professor Hooper says that the team’s next steps are to understand exactly how the amyloid-prion interaction kills off neurons.
"I’m certain that this will increase our understanding of Alzheimer’s disease even further, with the potential to reveal yet more drug targets," he said.
Dr Simon Ridley, Head of Research at Alzheimer’s Research UK, the UK’s leading dementia research charity, which part-funded the study, said: “Understanding the causes of Alzheimer’s is vital if we are to find a way of stopping the disease in its tracks. While these early-stage results should not be a signal for people to stock up on green tea and red wine, they could provide an important new lead in the search for new and effective treatments. With half a million people affected by Alzheimer’s in the UK, we urgently need treatments that can halt the disease – that means it’s crucial to invest in research to take results like these from the lab bench to the clinic.”
Treatment to prevent Alzheimer’s disease moves a step closer
A new drug to prevent the early stages of Alzheimer’s disease could enter clinical trials in a few years’ time according to scientists.
Alzheimer’s is the most common type of dementia, which currently affects 820,000 people in the UK, with numbers expected to more than double by 2050. One in three people over 65 will die with dementia.
The disease begins when a protein called amyloid-β (Aβ) starts to clump together in senile plaques in the brain, damaging nerve cells and leading to memory loss and confusion.
Professor David Allsop and Dr Mark Taylor at Lancaster University have successfully created a new drug which can reduce the number of senile plaques by a third, as well as more than doubling the number of new nerve cells in a particular region of the brain associated with memory. It also markedly reduced the amount of brain inflammation and oxidative damage associated with the disease.
The drug was tested on transgenic mice containing two mutant human genes linked to inherited forms of Alzheimer’s, so that they would develop some of the changes associated with the illness. The drug is designed to cross the blood-brain barrier and prevent the Aβ molecules from sticking together to form plaques.
Professor Allsop, who led the research and was the first scientist to isolate senile plaques from human brain, said: “When we got the test results back, we were highly encouraged. The amount of plaque in the brain had been reduced by a third and this could be improved if we gave a larger dose of the drug, because at this stage, we don’t know what the optimal dose is.”
The drug needs to be tested for safety before it can enter human trials, but, if it passes this hurdle, the aim would be to give the drug to people with mild symptoms of memory loss before they develop the illness.
“Many people who are mildly forgetful may go on to develop the disease because these senile plaques start forming years before any symptoms manifest themselves. The ultimate aim is to give the drug at that stage to stop any more damage to the brain, before it’s too late.”
Support for the research was given by Alzheimer’s Research UK, and the results are published in the open access journal PLOS ONE.
Right target, but missing the bulls-eye for Alzheimer’s
Alzheimer’s disease is the most common cause of late-life dementia. The disorder is thought to be caused by a protein known as amyloid-beta, or Abeta, which clumps together in the brain, forming plaques that are thought to destroy neurons. This destruction starts early, too, and can presage clinical signs of the disease by up to 20 years.
For decades now, researchers have been trying, with limited success, to develop drugs that prevent this clumping. Such drugs require a “target” — a structure they can bind to, thereby preventing the toxic actions of Abeta.
Now, a new study out of UCLA suggests that while researchers may have the right target in Abeta, they may be missing the bull’s-eye. Reporting in the Jan. 23 issue of the Journal of Molecular Biology, UCLA neurology professor David Teplow and colleagues focused on a particular segment of a toxic form of Abeta and discovered a unique hairpin-like structure that facilitates clumping.
"Every 68 seconds, someone in this country is diagnosed with Alzheimer’s," said Teplow, the study’s senior author and principal investigator of the NIH-sponsored Alzheimer’s Disease Research Center at UCLA. "Alzheimer’s disease is the only one of the top 10 causes of death in America that cannot be prevented, cured or even slowed down once it begins. Most of the drugs that have been developed have either failed or only provide modest improvement of the symptoms. So finding a better pathway for these potential therapeutics is critical."
The Abeta protein is composed of a sequence of amino acids, much like “a pearl necklace composed of 20 different combinations of different colors of pearl,” Teplow said. One form of Abeta, Abeta40, has 40 amino acids, while a second form, Abeta42, has two extra amino acids at one end.
Abeta42 has long been thought to be the toxic form of Abeta, but until now, no one has understood how the simple addition of two amino acids made it so much more toxic than Abeta40.
In his lab, Teplow and his colleagues used computer simulations in which they looked at the structure of the Abeta proteins in a virtual world. The researchers first created a virtual Abeta peptide that only contained the last 12 amino acids of the entire 42–amino-acid-long Abeta42 protein. Then, said Teplow, “we just let the molecule move around in a virtual world, letting the laws of physics determine how each atom of the peptide was attracted to or repulsed by other atoms.”
By taking thousands of snapshots of the various molecular structures the peptides created, the researchers determined which structures formed more frequently than others. From those, they then physically created mutant Abeta peptides using chemical synthesis.
"We studied these mutant peptides and found that the structure that made Abeta42 Abeta42 was a hairpin-like turn at the very end of the peptide of the whole Abeta protein," Teplow said.
The hairpin turn structure was not previously known in the detail revealed by the researchers, “so we feel our experiments were novel,” he said. “Our lab is the first to show that it is this specific turn that accounts for the special ability of Abeta42 to aggregate into clumps that we think kills neurons. Abeta40, the Abeta protein with two less amino acids at the end of the protein, did not do the same thing.”
Hopefully, the work of the Teplow laboratory presents what may the most relevant target yet for the development of drugs to fight Alzheimer’s disease, the researchers said.
(Source: uclahealth.org)
Potential Drug Target to Block Cell Death in Parkinson’s Disease
Oxidative stress is a primary villain in a host of diseases that range from cancer and heart failure to Alzheimer’s disease, Amyotrophic Lateral Sclerosis and Parkinson’s disease. Now, scientists from the Florida campus of The Scripps Research Institute (TSRI) have found that blocking the interaction of a critical enzyme may counteract the destruction of neurons associated with these neurodegenerative diseases, suggesting a potential new target for drug development.
These findings appear in the January 11, 2013 edition of The Journal of Biological Chemistry.
During periods of cellular stress, such as exposure to UV radiation, the number of highly reactive oxygen-containing molecules can increase in cells, resulting in serious damage. However, relatively little is known about the role played in this process by a number of stress-related enzymes.
In the new study, the TSRI team led by Professor Philip LoGrasso focused on an enzyme known as c-jun-N-terminal kinase (JNK). Under stress, JNK migrates to the mitochondria, the part of the cell that generates chemical energy and is involved in cell growth and death. That migration, coupled with JNK activation, is associated with a number of serious health issues, including mitochondrial dysfunction, which has long been known to contribute to neuronal death in Parkinson’s disease.
The new study showed for the first time that the interaction of JNK with a protein known as Sab is responsible for the initial JNK localization to the mitochondria in neurons. The scientists also found blocking JNK mitochondrial signaling by inhibiting JNK interaction with Sab can protect against neuronal damage in both cell culture and in the brain.
In addition, by treating JNK with a peptide inhibitor derived from a mitochondrial membrane protein, the team was able to induce a two-fold level of protection of neurons in the substantia nigra pars compacta, the brain region devastated by Parkinson’s disease.
The study noted that this inhibition leaves all other cell signaling intact, which could mean potentially fewer side effects in any future therapies.
“This may be a novel way to prevent neuron degeneration,” said LoGrasso. “Now we can try to make compounds that block that translocation and see if they’re therapeutically viable.”
European Project Aims To Create 1,500 New Stem Cell Lines
A joint public-private collaboration between the European Union and Europe’s pharmaceutical industry, called the StemBANCC project, will spend nearly 50 million euros to create 1,500 pluripotent stem cell lines. But the initiative’s goal isn’t to find a stem cell-based cure for diabetes or Alzheimer’s disease. They hope instead that their stem cell lines will prove to be faster and more effective drug screens in the search for drugs to fight these and other conditions.
A frustrating problem in medical research is the inadequacy of animal models. All too often a treatment works great in laboratory rats or mice but then its efficacy fails to repeat in human trials. But researchers are beginning to capitalize on the potential of stem cells – not as cures, but as means to finding cures.
Scientists are becoming more adept at turning skin cells into pluripotent stem cells, which can then be converted to other cell types such as neurons or heart cells. And because these are human cells they are superior to animal models for drug screening or toxicity testing. Human cell lines have been used for many years, but before pluripotent stem cells creating cell lines involved immortalizing the cells and thus drastically changing their physiology.
The goal of StemBANCC is to use these human-induced pluripotent stem cells as a drug discovery platform to treat the following 8 common diseases: Alzheimer’s disease, Parkinson’s disease, autism, schizophrenia, bipolar disorder, migraine, pain and diabetes. Studying these conditions typically involves creating an animal model, such as a rat that exhibits some behavioral hallmarks of autism after being given valproic acid. The cells from StemBANCC would improve upon animal models by providing, not only cells from humans but cells from patients with the actual disorders being studied. Skin cells gotten from a schizophrenia patient and converted (via pluripotency) to neurons, for instance, would give scientists a powerful tool with which to screen drugs.
Led by Oxford University, StemBANCC will involve 10 pharmaceutical companies and 23 academic institutions across 11 different countries. Part of the Innovative Medicines Initiative that pairs the European Union and the pharmaceutical industry. The EU is contributing 26 million euros ($33.5 million). Another 21 million euros ($27 million) are coming from the pharmaceutical industry. StemBANCC’s “kick-off” meeting took place in 2012 in Basel, Switzerland.
Zameel Cader, neurologist at the University of Oxford and a leader on the project, told Nature, “We’re specifically trying to develop a panel of lines across a range of diseases that are important to address. There isn’t another institution that’s doing this at the same scale across the same range of diseases.”
The hype surrounding stem cells typically extolls their virtues as a miraculous ‘cure all’ replacing damaged or diseased cells with new, healthy ones. And while stem cells have given blind people back part of their sight and have shown to restore some hearing in animals or even help paralyzed ones walk again in the lab, mainstream cures derived from stem cells are still rare. In the meantime, places like StemBANCC can pursue the less sexy, perhaps, but more reachable near term benefits of stem cells.
Study paves way to design drugs aimed at multiple protein targets at once
An international research collaboration led by scientists at the University of North Carolina School of Medicine and the University of Dundee, in the U.K., have developed a way to efficiently and effectively make designer drugs that hit multiple protein targets at once.
This accomplishment, described in the Dec. 13, 2012 issue of the journal Nature, may prove invaluable for developing drugs to treat many common human diseases such as diabetes, high blood pressure, obesity, cancer, schizophrenia, and bi-polar disorder.
These disorders are called complex diseases because each have a number of genetic and non-genetic influences that determine susceptibility, i.e., whether someone will get the disease or not.
“In terms of the genetics of schizophrenia we know there are likely hundreds of different genes that can influence the risk for disease and, because of that, there’s likely no single gene and no one drug target that will be useful for treating it, like other common complex diseases,” said study co-leader, Brian L. Roth, MD, PhD, Michael J. Hooker Distinguished Professor of Pharmacology in the UNC School of Medicine, professor in the Division of Chemical Biology and Medicinal Chemistry in the UNC Eshelman School of Pharmacy, and director of the National Institute of Mental Health Psychoactive Drug Screening Program.
In complex neuropsychiatric conditions, infectious diseases and cancer, Roth points out that for the past 20 years drug design has been selectively aimed at a single molecular target, but because these are complex diseases, the drugs are often ineffective and thus many never reach the market.
Moreover, a drug that acts on a single targeted protein may interact with many other proteins. These undesired interactions frequently cause toxicity and adverse effects. “And so the realization has been that perhaps one way forward is to make drugs that hit collections of drug targets simultaneously. This paper provides a way to do that,” Roth said.
The new way involves automated drug design by computer that takes advantage of large databases of drug-target interactions. The latter have been made public through Roth’s lab at UNC and through other resources.
Automated drug design using synthetic DNA self-assembly
Using a simple “drag-and-drop” computer interface and DNA self-assembly techniques, Parabon NanoLabs researchers have developed a new automated method of drug development that could reduce the time required to create and test medications, with the support of an NSF Technology Enhancement for Commercial Partnerships grant.
“We can now ‘print,’ molecule by molecule, exactly the compound that we want,” says Steven Armentrout, the principal investigator on the NSF grants and co-developer of Parabon’s technology.
“What differentiates our nanotechnology from others is our ability to rapidly, and precisely, specify the placement of every atom in a compound that we design.”
The Parabon Essemblix Drug Development Platform combines computer-aided design (CAD) software with nanoscale fabrication technology, developed in partnership with Janssen Research & Development, LLC, part of the Janssen Pharmaceutical Companies of Johnson & Johnson.
To develop new drugs, scientists can use the CAD software to design molecular pieces with specific, functional components. The software then optimizes the design using a cloud supercomputing platform that uses proprietary algorithms to search for specific sets of DNA sequences that can self-assemble those components.
“When designing a therapeutic compound, we combine knowledge of the cell receptors we are targeting or biological pathways we are trying to affect with an understanding of the linking chemistry that defines what is possible to assemble,” says Hong Zhong, senior research scientist at Parabon and a collaborator on the grants. “It’s a deliberate and methodical engineering process, which is quite different from most other drug development approaches in use today.”
Lipid metabolism regulates the activity of adult neural stem cells
Neural stem cells generate thousands of new neurons every day in two regions of the adult brain: the subventricular zone of the lateral ventricles and the dentate gyrus of the hippocampus. This process, called adult neurogenesis, is critical for a number of processes implicated in certain forms of learning and memory. Impaired adult neurogenesis has been associated with a number of diseases such as depression, epilepsy, and Alzheimer’s disease.
A team led by Sebastian Jessberger, Professor of Neurosciences at the Brain Research Institute, has now identified a novel mechanism that plays a key role in adult neurogenesis and is required for the life-long activity of neural stem cells. Prof. Jessberger believes that “this finding will hopefully give us a new target to develop novel drugs against depression or neurodegenerative diseases”. The results of this study were published on December 2nd in the scientific journal Nature.
Stem cells produce their own lipids
Researchers in his group could show that stem cells depend on glucose-derived production of new fatty acids and lipids. When the key enzyme of this pathway, fatty acid synthase (Fasn), is blocked in neural stem cells, they loose their ability to divide which results in a reduction in newborn neurons.
To prevent the constant division of neural stem cells, this pathway is regulated by a protein called Spot14, which inhibits lipid synthesis. Controlling Fasn activity is important to make sure that stem cells do not divide too often, which could lead to a premature exhaustion or depletion of the stem cell pool. Surprisingly, the metabolic state of neural stem cells seems to be fundamentally distinct from their daughter cells (newborn neurons) and other dividing cells in the central nervous system. These other cell types are able to take up lipids from the blood stream and use them as important structural components of cell membranes but also for signaling events and as an energy source.
Potential target for new drugs
The study published by the Jessberger group has identified a novel target to pharmacologically enhance the activity of neural stem cells in diseases that are associated with reduced levels of newborn neurons, such as depression.
Marlen Knobloch, postdoc in the Jessberger lab and first author of the study, says: “Currently, we have to understand in much greater detail why neural stem cells are in this distinct metabolic state; to this end, we are currently performing experiments in the lab with the aim to enhance neurogenesis through manipulation of lipid metabolism”. However, one must not place too high expectations for the quick development of novel drugs, although for Simon Braun, co-first author of the study, “the hope certainly is to increase the number of newborn neurons by targeting lipid metabolism in the human brain”.
University of Minnesota researchers find new target for Alzheimer’s drug development
Researchers at the University of Minnesota’s Center for Drug Design have developed a synthetic compound that, in a mouse model, successfully prevents the neurodegeneration associated with Alzheimer’s disease.
In the pre-clinical study, researchers Robert Vince, Ph.D.; Swati More, Ph.D.; and Ashish Vartak, Ph.D., of the University’s Center for Drug Design, found evidence that a lab-made compound known as psi-GSH enables the brain to use its own protective enzyme system, called glyoxalase, against the Alzheimer’s disease process.
The discovery is published online in the American Chemical Society journal ACS Chemical Neuroscience and presents a new target for the design of anti-Alzheimer’s and related drugs.
“While most other drugs under development and on the market attempt to slow down or reverse the Alzheimer’s processes, our approach strikes at a root cause by enabling the brain itself to fight the disease at a very early stage,” said Vince, the study’s lead researcher and director of the Center for Drug Design. “As is the case with all drug development, these studies need to be replicated in human patients before coming to any firm conclusions.”