Creating new drugs to combat disease and illness requires the completion of a complex 3D jigsaw. The shape of the drug must be right to allow it to bind to a specific disease-related protein and to work effectively, and this shape is determined by the core framework of the molecule.

Now a team from the Astbury Centre for Structural Molecular Biology at the University of Leeds has developed a new approach which allows the creation of molecules with an extraordinarily wide range of molecular frameworks and, hence, shapes. The new molecules are likely to have a wide range of biological functions, which means they could be valuable starting points for the discovery of new drugs.

Says lead researcher Professor Adam Nelson of the University’s School of Chemistry: “Nature has created hundreds of thousands of molecules that have different frameworks and biological purposes, but in the global pursuit of new drugs, chemists from around the world are racing to create new molecules with functions not seen in nature.”

The newly created molecules are being shared with colleagues in the Faculties of Biological Sciences and Medicine and Health to see if specific new molecular frameworks match the requirements of their own research.

Of the 30 million or so synthetic molecules made throughout the history of organic chemistry, many are based on an extremely small number of core frameworks, with the main differences being the groups attached at the periphery. “Making collections of similar molecules is great for optimising a biological property,” says Professor Nelson, “but to put it simply, if researchers need a cube-shaped molecule to target a particular protein, they may well find that they can only choose from libraries stocked with millions of sphere-shaped ones.”

Co-researcher Dr Stuart Warriner added: “Making molecules is a bit like making something using lego bricks. Up until now we’ve only really become good at making, say, the equivalent of a lego car or train. There might be 30 million synthetic molecules registered, but there’s probably several million of these that are the equivalent of lego cars they may have different wheels and wing mirrors, but their fundamental shape is essentially the same. We’ve not really scratched the surface of the possible structures that could be made. This lack of variety in the core shape of molecules may well limit the range of proteins that medicinal chemists can target.”

The Leeds approach makes use of ‘metathesis’, a reaction that won the 2005 Nobel Prize in Chemistry.

Explains Professor Nelson: “We take simple building blocks, a bit like the amino acids that make up peptides, and we assemble them in different sequences using three simple reactions to link them together in a chain. The key difference is that we then add the catalyst which initiates a ’scaffold reprogramming reaction’, which ripples down the chemical chain and restitches the molecule together in a completely different way each time.

“It’s a bit like a molecular square dance, where atoms in the molecule swap partners - and the exciting thing is that we can change the building blocks again and again in different combinations as a really powerful way to vary the core frameworks that result. The potential of this process is enormous,” he says.

The team from Leeds have used their approach to prepare molecules with 84 distinct molecular frameworks and about two-thirds of the frameworks are unprecedented in the history of organic chemistry. The work is a huge leap forward from landmark research reported in 2003, which resulted in the creation of six frameworks in a single process. It is also a significant improvement on more recent research in which around 30 frameworks were created using a complex combination of different reactions.

The team has deliberately chosen to prepare molecules with structural features that are similar to those found in natural products: “For example we know that putting oxygen atoms on every other carbon atom is something that frequently occurs in nature and has evolved for a useful purpose” says Professor Nelson. “We’re not aiming to improve on existing natural products or drugs - we want to create molecules with functions that nature’s not got round to making yet, or something that would only evolve naturally with new selection pressures that would make it beneficial for the organism.”

Work has already begun across campus to screen the molecules, which are already yielding “promising” results. The team are considering patenting molecules with novel biological functions.

The findings may offer a new weapon against this autoimmune disease, formerly called juvenile-onset diabetes, for which few drugs have been developed to address the underlying causes, the lead scientists say.

“There are very few drugs to treat type 1 diabetes, especially after disease onset, so this benefit, with a drug already proven to be safe and effective in cancer patients, is very promising,” said Jeffrey Bluestone, PhD, director of the Diabetes Center at UCSF and an expert in the study of autoimmunity. “The fact that the treated mice maintained normal blood glucose levels for some time after the drug treatment was stopped suggests that imatinib and sunitinib may be ‘reprogramming’ their immune systems in a permanent way.”

Bluestone is the A.W. and Mary Margaret Clausen Distinguished Professor of the Diabetes Center at UCSF and a senior author on the paper.

Both drugs treat cancer by inhibiting a small subset of the more than 500 tyrosine kinases, which are enzymes that modify cells’ signaling proteins through a simple biochemical change. Kinases are ubiquitous agents of cell growth and proliferation, and are also involved in many diseases such as inflammation and cancer. In the immune system, tyrosine kinases are thought to be key to nearly every aspect of immunity, from the signaling that initiates a response by the immune system’s T and B cells to later stages of inflammation that can cause tissue damage.

Because type 1 diabetes is caused by an autoimmune response that destroys insulin-secreting cells in the pancreas, the scientists sought to determine if one or more of the tyrosine kinases blocked by the two cancer drugs might also be responsible for the destructive inflammation in the pancreas. If so, the drugs might be promising candidates to treat diabetes.

Using a well-established mouse model for diabetes, known as the non-obese diabetic (NOD) mouse, they found that treating mice with imatinib or sunitinib before the onset of autoimmune diabetes prevented the development of the disease. Findings showed that the drugs’ benefits lasted well after the seven-week treatment. Studies with mice that already had diabetes showed that imatinib put the disease into permanent remission in 80 percent of the mice after only eight to 10 weeks of treatment.

The scientists aimed to determine which of the tyrosine kinases targeted by the two cancer drugs might be responsible for triggering diabetes. To their surprise, a few of the drugs’ primary targets did not appear crucial to the diabetes treatment’s success.

Instead, they found that the drugs’ rapid benefit appears to derive from the ability to block receptors of a tyrosine kinase not known to be implicated in diabetes, an enzyme known as platelet-derived growth factor receptor, or PDGFR. This kinase regulates cell growth and division, and also plays a key role in inflammation in a variety of settings.

“This study opens up a new area of research in the field of type 1 diabetes, and importantly, opens up exciting opportunities for developing new therapies to treat this disease and other autoimmune diseases,” said Arthur Weiss, MD, PhD, UCSF professor of rheumatology and a senior author on the paper.

Weiss is the Ephraim P. Engleman Distinguished Professor and chief of rheumatology at UCSF.

The scientists will continue to study the effects of PDGFR in type 1 diabetes and have now applied for funding to perform a safety and efficacy clinical trial in patients.

Source: University of California - San Francisco

Researchers at Northwestern University’sFeinberg School of Medicine wondered if the brains of the elderly with still laser sharp memory — called “super aged” — were somehow different than everyone else’s. So, instead of the usual approach in which scientists explore what goes wrong in a brain when older people lose their memory, they investigated what goes right in an aging brain that stays nimble.

Now they have a preliminary answer. Scientists examined the brains of five deceased people considered super aged because of their high performance on memory tests when they were more than 80 years old and compared them to the brains of elderly, non-demented individuals. Researchers found the super aged brains had many fewer fiber-like tangles than the brains of those who had aged normally. The tangles consist of a protein called tau that accumulates inside brain cells and is thought to eventually kill the cells. Tangles are found in moderate numbers in the brains of elderly and increase substantially in the brains of Alzheimer’s disease patients.

“This new finding in super aged brains is very exciting,” said Changiz Geula, principal investigator of the study and a research professor of neurology at the Cognitive Neurology and Alzheimer’s Disease Center at Northwestern’s Feinberg School. “It was always assumed that the accumulation of these tangles is a progressive phenomenon through the aging process. But we are seeing that some individuals are immune to tangle formation and that the presence of these tangles seems to influence cognitive performance.” Individuals who have few tangles perform at superior levels, while those who have more tangles appear to be normal for their age, Geula noted.

Geula will present his findings Sunday, November 16, at the Society for Neuroscience annual meeting in Washington, D.C.

The number of plaques in the brains of the super aged was similar to that in the brains of the normally aging group. The plaque is an aggregation of protein called amyloid that becomes deposited outside the brain cell and disrupts communication between neurons. Like tangles, plaques also are found in modest numbers in the brains of aged individuals and show a dramatic increase in number in Alzheimer’s disease.

Geula said the lower number of tangles in the super aged appears to be the critical difference in maintaining memory skills.

Some of the super aged in the study performed memory tasks at the level of people who were about 50 years old. For example, after being told a story, they were able to remember it immediately after and still accurately recall its details 30 minutes later. They also remembered a list of 15 words and recalled these words equally well when tested after 30 minutes.

Geula said new research will focus on what makes cells in super aged brains more resistant to tangle formation. “We want to see what protects the brains of these individuals against the ravages that cause memory loss,” he said. ” Understanding the specific genetic and molecular characteristics of the brains that makes them resistant, someday may lead to the ability to protect average brains from memory loss. ”

Geula’s research is part of a larger super aging study at Northwestern’s Cognitive Neurology and Alzheimer’s Disease Center (CNADC). The study’s goal is to identify high functioning individuals over 80 and investigate what factors are important to maintain this ability into old age. A number of super aged individuals have been identified and are being followed up annually with tests of cognitive abilities. Recruitment continues for the study.

The research team also found that expression of the protein, known as PEA-15, is an independent indicator of a woman’s prospects for surviving ovarian cancer, said senior author Naoto T. Ueno, M.D., Ph.D. associate professor of breast medical oncology.

An analysis of ovarian cancer tumors from 395 women showed those with high expression of the PEA-15 had a median survival time of 50.2 months compared with 33.5 months for women with low levels of the protein in their tumors.

“These findings provide a foundation for developing a PEA-15 targeted approach for ovarian cancer and for clarifying whether this protein is a novel biomarker that can predict patient outcomes,” Ueno said.

Ovarian cancer kills about 15,000 women in the United States annually, and is notoriously hard to diagnose in its early stages, when it is also most optimal to treat.

A series of lab experiments by first author Chandra Bartholomeusz, M.D., Ph.D., showed that high expression of PEA-15 inhibits the growth of ovarian cancer cells by killing cells via autophagy, or self-cannibalization, rather than by apoptosis. Removing PEA-15 from ovarian cancer cells led to a 115 percent increase in the number of cells compared with a control group of cells that still had the protein.

In apoptosis, defective cells die from self-induced damage to their nuclei and DNA complex. Autophagy kills when a cell entraps parts of its cytoplasm in membranes and digests the contents, leaving a cavity. When this goes on long enough, the cell essentially eats itself until it dies, its cytoplasm riddled with cavities.

Location, location, location

Ueno’s research team has found that the protein works to inhibit cancer in two distinct ways depending on its location in the cell.

First, PEA-15 inhibits one of the prominent actors in the growth, differentiation and mobility of cells, a protein called extracellular signaling related kinase, or ERK. Activated ERK in the cell nucleus fuels cancer growth. The research team earlier found that PEA-15 binds to ERK in the nucleus and moves it out into the cytoplasm, preventing its growth effects.

Now they’ve found that PEA-15 in the cytoplasm induces autophagy in cancer cells, a second method of inhibiting cancer growth. “These two very different actions by PEA-15 are based on the location of the protein,” Ueno said.

ERK is an inviting target for cancer therapy, Ueno noted, but so far no one has been able to develop a successful ERK inhibitor.

“PEA-15 offers us a new dimension for potentially targeting ERK,” Ueno said. “We’ve shown with high levels of PEA-15, women with ovarian cancer are surviving longer.” Levels of the protein in tumors also might affect how other drugs work against the disease. Similar research is under way in breast cancer with. PEA-15, which is short for phospho-enriched protein in astrocytes.

Dr. Daniel Gardner, co-editor of the special issue, said, We on the Neuroscience Information Framework project team selected Neuroinformatics as the perfect vehicle for our comprehensive set of peer-reviewed papers detailing the goals, design and operation of the NIF. We are particularly grateful that Humana Press is making the entire issue available in open access format to the neuroscience and neuroinformatics community.

The Neuroscience Information Framework is designed to serve a broad set of neuroscience investigators working on many problems, using many techniques and preparations. It enables users to discover global neuroscience web resources that cut across traditional boundaries from experimental, clinical and translational neuroscience databases to knowledge bases, atlases, and genetic and genomic resources. Unlike general search engines, the NIF provides deeper access to a more focused set of resources that are relevant to neuroscience, search strategies tailored to neuroscience, and access to content that is traditionally hidden from web search engines. The NIF may be viewed at http://nif.nih.gov and other sites as they appear online. All components of the NIF are available Open Source to encourage multiple community, institution and publisher development of NIF-compatible portals and web resources.

This special issue of Neuroinformatics, edited by Gardner and Dr. Maryann Martone, presents the culmination of NIF development to the neuroscience and neuroinformatics community. An introductory White Paper summarizes the project and its development in the context of the present and future of neuroinformatics, as well as the challenges of serving the entire neuroscience community. Three articles define the enabling terminology thrusts of the project, two describe design methodology and components, and two detail specific components: a PubMed LinkOut Broker and a linked neuromorphology database.

Neuroinformatics is one of the leading journals in this emerging field, leveraging computer and informational techniques in the service of neuroscience. Humana Press, a publisher of medical and scientific books and journals, is part of Springer Science+Business Media, one of the worlds leading suppliers of scientific and specialist literature.

According to the American College of Obstetricians and Gynecologists, morning sickness affects 70-85% of women. The symptoms typically start during the first nine weeks of pregnancy, ranging from mild to severe. Severe cases can lead to hospitalization. Thats why its best to control morning sickness from the outset. Unfortunately, many women think their options are limited to the crackers and ginger ale routine or prescription drugs. But now, increasing numbers of expectant moms across the U.S. are discovering an effective, natural alternative to treat their morning sickness.

Thats where Roshan Kaderali enters the picture. Kaderali, an RN who has practiced as an obstetrical nurse, midwife, childbirth educator and a doula, has worked in the medical field more than 40 years. Shes also the founder and CEO of MOM Enterprises and creator of Babys Bliss and Mommys Bliss (www.mommysbliss.com)a line of all-natural products created exclusively for babies and expectant mothers. Kaderalis international upbringing and education led her to discover natural remedies that are proven staples in households around the world.

The issues expectant moms face are universal, says Kaderali. They all want to do whats best for their babies. With morning sickness, many women think they have to just tough it out because they dont want to take a prescription drug. But toughing it out isnt good for mom or baby either. Women who are pregnant need folic acid and other essential nutrients. If theyre throwing up or not eating because of morning sickness, that impacts everyones health.

Thats what led Kaderali to work with an FDA compliant laboratory to create Morning Sickness Magic, a natural supplement to treat morning sickness. From her decades of experience working with pregnant women, Kaderali already knew of various natural remedies that would tame the symptoms of morning sickness. But she couldnt find them in a combined, easy-to-take formulation.

Vitamin B6 and ginger have both been recommended individually for morning sickness, says Kaderali. But they actually work much better together. Thats because ginger, when taken by itself, can take the edge off of nausea in a short period of time, but its not long-lasting. On the other hand, B6 levels must be built up and sustained in the bloodstream to be effective thats why some women resort to getting Vitamin B shots.

Because morning sickness afflicts so many pregnant women, obstetricians are besieged with requests from their patients to help quell the symptoms. Up until recently, the options have been limited and not overly effective. Thats why the natural formulation in Morning Sickness Magic has been such a hit among expectant moms and their doctors.

This is the first formula to combine B6, ginger, and other anti-nausea ingredients, says Kaderali. Its safe for mothers and their unborn babiesobstetricians across the country are recommending it and distributing it to their patients. Its actually been the best selling morning sickness formula in the U.S. for the past 5 years. Weve received tons of emails from expectant mothers who are so relieved that their morning sickness has disappeared.

The standard of care for patients with locally advanced non-small-cell lung cancer is chemotherapy and
radiation therapy. Unfortunately, these aggressive treatments can put patients at risk of a serious side effect
called bone marrow toxicity that can lead to delayed or missed treatments, hospitalizations and growth
problems.

To try to alleviate this side effect, doctors at M.D. Anderson Cancer Center examined 142 patients with
locally advanced non-small cell lung cancer. Of those, 75 patients received chemotherapy plus a type of
targeted photon (X-ray) radiation therapy called intensity modulated radiation therapy (IMRT). The remaining
67 patients received chemotherapy and proton beam therapy. Proton beam therapy is a type of external beam
therapy that uses protons rather than photons to kill fast growing cancer cells.
Because proton therapy allows us to control the radiation differently than other types of external beam
radiation therapy, we were hopeful that we could keep radiation away from critical structures, like the bones to avoid bone marrow toxicity, said Ritsuko Komaki, M.D., FASTRO, a radiation oncologist at M.D. Anderson
Cancer Center in Houston.

After a follow-up time of 17 months, researchers found patients who received proton therapy with
chemotherapy had a significant reduction in bone marrow toxicity compared to patients who received IMRT
and chemotherapy. These findings suggest that using proton therapy over other types of radiation may allow
doctors to give a higher dose of radiation without compromising the chemotherapy schedule to the lung tumor
while avoiding some debilitating side effects, like bone marrow toxicity.
These results are very promising for people with locally advanced lung cancer, said Dr. Komaki.
However, we need to now confirm these findings with a randomized trial.

Normally, immune cells develop to recognise foreign material antigens; including bacteria - so that they can activate a response against them. Immune cells that would respond to ’self’ and therefore attack the body’s own cells are usually destroyed during development. If any persist, they are held in check by special regulatory cells that provide a sort of autoimmune checkpoint. A key player in these regulatory cells is a molecule called Foxp3. People who lack or have mutated versions of the Foxp3 gene lack or have dysfunctional immune regulation, which causes dramatic autoimmune disease.

Scientists at the Medical Research Council’s Laboratory of Molecular Biology in Cambridge, and funded by the Arthritis Research Campaign, have genetically engineered a drug-inducible form of Foxp3. Using this, scientists can ’switch’ developing immune cells into regulatory cells that are then capable of suppressing the immune response.

Dr. Alexander Betz, Group Leader at the MRC laboratory, explains: “We have generated a modified form of Foxp3 which can be introduced into immune cells using genetic engineering techniques and then activated by a simple injection. When administered to and activated in animal models of arthritis, the modified cells inhibit or even reverse the disease process.”

Further work is now aimed at elucidating the detailed molecular mechanisms involved in Foxp3 function, and transferring the experimental approach to human cells.

“First, we will develop a human Foxp3 factor and then assess its function in human arthritis models,” said Dr Betz. “To be viable as a therapeutic option, the regulatory cells must fulfill certain criteria; they must be tissue matched to the patient for compatibility; they must only block the targeted disease and not the whole body immune response; and they have to home correctly to their target tissue. Establishing these criteria will be the key focus of our research.

“If Foxp3 functions as a key developmental switch in human immune cells, there is potential for a new avenue of therapy development that could transform arthritis treatment is substantial,” he added.

Public Library of Science

“We found a unique approach for delivering drugs to the brain,” says William A. Banks, M.D., professor of geriatrics and pharmacological and physiological science at Saint Louis University. “We’re turning off the guardian that’s keeping the drugs out of the brain.”

The brain is protected by the blood-brain barrier (BBB), a gate-keeping system of cells that lets in nutrients and keeps out foreign substances. The blood-brain barrier passes no judgment on which foreign substances are trying to get into the brain to treat diseases and which are trying to do harm, so it blocks them without discrimination.

“The problem in treating a lot of diseases of the central nervous system such as Alzheimer’s disease, HIV and stroke is that we can’t get drugs past the blood-brain barrier and into the brain,” says Banks, who also is a staff physician at Veterans Affairs Medical Center in St. Louis.

“Our new research shows a way of getting a promising treatment for these types of devastating diseases to where they need to be to work.”

The therapy known as PACAP27 — is a hormone produced by the body that is a general neuro-protectant. PACAP stands for pituitary adenylate cyclase-activating polypeptide. “It is a general protector of the brain against many types of insult and injury,” Banks says.

He compares a specific guarding mechanism in the BBB — efflux pumps to bouncers at exclusive nightclubs. While they welcome those on the approved guest list, they look for trouble-makers trying to crash the party, refuse to let them in and evict them if they do get in.

The scientists isolated the particular gatekeeper than evicts PACAP27. Then they designed an antisense, a specific molecule that turned off the impediment.

“We went after the guard and essentially told him to go on break for a while so PACAP27 could get into the brain,” Banks says.

They used mouse models of Alzheimer’s disease and stroke to test what would happen if PACAP27 could get into the brain.

“We reversed the symptoms of the illnesses,” Banks says. “The mice that had a version of Alzheimer’s disease became smarter and in the stroke model, we reduced the amount of damage caused by the blockage of blood to the brain and improved brain recovery.”

Simply turning off the gatekeeper that kept PACAP27 out of the brain allowed enough of the hormone that already is in the body to get inside the brain, where it effectively treated strokes. However, the mice that had a version of Alzheimer’s disease needed both an extra dose of PACAP27 and the antisense that turned off the gatekeeper to improve learning.

“These findings are significant for three reasons. We have found a therapy that reverses symptoms of Alzheimers’s disease and stroke in a mouse model. We have isolated the particular roadblock that keeps the treatment from getting into the brain. And we have found a way to finesse that obstacle so the medicine can get into the brain to do its work,” Banks says. “This could have implications in treating many diseases of the central nervous system.”

The findings were published in the Nov. 12 early online issue of the Journal of Cerebral Blood Flow & Metabolism.