MSU research pushes promising molecule toward clinical trials for treatment of neurological disorders

Research at Michigan State University, published in the Journal of Biological Chemistry, shows that a small "molecular tweezer" keeps proteins from clumping, or aggregating, the first step of neurological disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease.

The results are pushing the promising molecule toward clinical trials and actually becoming a new drug, said Lisa Lapidus, MSU associate professor of physics and astronomy and co-author of the paper.

"By the time patients show symptoms and go to a doctor, aggregation already has a stronghold in their brains," she said. "In the lab, however, we can see the first steps, at the very place where the drugs could be the most effective. This could be a strong model for fighting Parkinson's and other diseases that involve neurotoxic aggregation."

Lapidus' lab uses lasers to study the speed of protein reconfiguration before aggregation, a technique Lapidus pioneered. Proteins are chains of amino acids that do most of the work in cells. Scientists understand protein structure, but they don't know how they are built - a process known as folding.

Lapidus' lab has shed light on the process by correlating the speed at which an unfolded protein changes shape, or reconfigures, with its tendency to clump or bind with other proteins. If reconfiguration is much faster or slower than the speed at which proteins bump into each other, aggregation is slow, but if reconfiguration is the same speed, aggregation is fast. 

Srabasti Acharya, lead author and doctoral candidate in Lapidus' lab, tested the molecule, CLR01, (see structure) which was patented jointly by researchers at the University of Duisburg-Essen (Germany) and UCLA. CLR01 binds to the protein and prevents aggregation by speeding up reconfiguration. It's like a claw that attaches to the amino acid lysine, which is part of the protein.

This work was preceded by Lapidus' research involving the spice curcumin. While the spice molecules put the researchers on a solid path, the molecules weren't viable drug candidates because they cannot cross the blood-brain barrier, or BBB, the filter that controls what chemicals reach the brain.

MSU research pushes promising molecule toward clinical trials for treatment of neurological disorders

MSU research pushes promising molecule toward clinical trials for treatment of neurological disorders

Research at Michigan State University, published in the Journal of Biological Chemistry, shows that a small "molecular tweezer" keeps proteins from clumping, or aggregating, the first step of neurological disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease.

The results are pushing the promising molecule toward clinical trials and actually becoming a new drug, said Lisa Lapidus, MSU associate professor of physics and astronomy and co-author of the paper.

"By the time patients show symptoms and go to a doctor, aggregation already has a stronghold in their brains," she said. "In the lab, however, we can see the first steps, at the very place where the drugs could be the most effective. This could be a strong model for fighting Parkinson's and other diseases that involve neurotoxic aggregation."

Lapidus' lab uses lasers to study the speed of protein reconfiguration before aggregation, a technique Lapidus pioneered. Proteins are chains of amino acids that do most of the work in cells. Scientists understand protein structure, but they don't know how they are built - a process known as folding.

Lapidus' lab has shed light on the process by correlating the speed at which an unfolded protein changes shape, or reconfigures, with its tendency to clump or bind with other proteins. If reconfiguration is much faster or slower than the speed at which proteins bump into each other, aggregation is slow, but if reconfiguration is the same speed, aggregation is fast. 

Srabasti Acharya, lead author and doctoral candidate in Lapidus' lab, tested the molecule, CLR01, (see structure) which was patented jointly by researchers at the University of Duisburg-Essen (Germany) and UCLA. CLR01 binds to the protein and prevents aggregation by speeding up reconfiguration. It's like a claw that attaches to the amino acid lysine, which is part of the protein.

This work was preceded by Lapidus' research involving the spice curcumin. While the spice molecules put the researchers on a solid path, the molecules weren't viable drug candidates because they cannot cross the blood-brain barrier, or BBB, the filter that controls what chemicals reach the brain.

MSU research pushes promising molecule toward clinical trials for treatment of neurological disorders

MSU research pushes promising molecule toward clinical trials for treatment of neurological disorders

Research at Michigan State University, published in the Journal of Biological Chemistry, shows that a small "molecular tweezer" keeps proteins from clumping, or aggregating, the first step of neurological disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease.

The results are pushing the promising molecule toward clinical trials and actually becoming a new drug, said Lisa Lapidus, MSU associate professor of physics and astronomy and co-author of the paper.

"By the time patients show symptoms and go to a doctor, aggregation already has a stronghold in their brains," she said. "In the lab, however, we can see the first steps, at the very place where the drugs could be the most effective. This could be a strong model for fighting Parkinson's and other diseases that involve neurotoxic aggregation."

Lapidus' lab uses lasers to study the speed of protein reconfiguration before aggregation, a technique Lapidus pioneered. Proteins are chains of amino acids that do most of the work in cells. Scientists understand protein structure, but they don't know how they are built - a process known as folding.

Lapidus' lab has shed light on the process by correlating the speed at which an unfolded protein changes shape, or reconfigures, with its tendency to clump or bind with other proteins. If reconfiguration is much faster or slower than the speed at which proteins bump into each other, aggregation is slow, but if reconfiguration is the same speed, aggregation is fast. 

Srabasti Acharya, lead author and doctoral candidate in Lapidus' lab, tested the molecule, CLR01, (see structure) which was patented jointly by researchers at the University of Duisburg-Essen (Germany) and UCLA. CLR01 binds to the protein and prevents aggregation by speeding up reconfiguration. It's like a claw that attaches to the amino acid lysine, which is part of the protein.

This work was preceded by Lapidus' research involving the spice curcumin. While the spice molecules put the researchers on a solid path, the molecules weren't viable drug candidates because they cannot cross the blood-brain barrier, or BBB, the filter that controls what chemicals reach the brain.

MSU research pushes promising molecule toward clinical trials for treatment of neurological disorders

MSU research pushes promising molecule toward clinical trials for treatment of neurological disorders

Research at Michigan State University, published in the Journal of Biological Chemistry, shows that a small "molecular tweezer" keeps proteins from clumping, or aggregating, the first step of neurological disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease.

The results are pushing the promising molecule toward clinical trials and actually becoming a new drug, said Lisa Lapidus, MSU associate professor of physics and astronomy and co-author of the paper.

"By the time patients show symptoms and go to a doctor, aggregation already has a stronghold in their brains," she said. "In the lab, however, we can see the first steps, at the very place where the drugs could be the most effective. This could be a strong model for fighting Parkinson's and other diseases that involve neurotoxic aggregation."

Lapidus' lab uses lasers to study the speed of protein reconfiguration before aggregation, a technique Lapidus pioneered. Proteins are chains of amino acids that do most of the work in cells. Scientists understand protein structure, but they don't know how they are built - a process known as folding.

Lapidus' lab has shed light on the process by correlating the speed at which an unfolded protein changes shape, or reconfigures, with its tendency to clump or bind with other proteins. If reconfiguration is much faster or slower than the speed at which proteins bump into each other, aggregation is slow, but if reconfiguration is the same speed, aggregation is fast. 

Srabasti Acharya, lead author and doctoral candidate in Lapidus' lab, tested the molecule, CLR01, (see structure) which was patented jointly by researchers at the University of Duisburg-Essen (Germany) and UCLA. CLR01 binds to the protein and prevents aggregation by speeding up reconfiguration. It's like a claw that attaches to the amino acid lysine, which is part of the protein.

This work was preceded by Lapidus' research involving the spice curcumin. While the spice molecules put the researchers on a solid path, the molecules weren't viable drug candidates because they cannot cross the blood-brain barrier, or BBB, the filter that controls what chemicals reach the brain.

MSU research pushes promising molecule toward clinical trials for treatment of neurological disorders

MSU research pushes promising molecule toward clinical trials for treatment of neurological disorders

Research at Michigan State University, published in the Journal of Biological Chemistry, shows that a small "molecular tweezer" keeps proteins from clumping, or aggregating, the first step of neurological disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease.

The results are pushing the promising molecule toward clinical trials and actually becoming a new drug, said Lisa Lapidus, MSU associate professor of physics and astronomy and co-author of the paper.

"By the time patients show symptoms and go to a doctor, aggregation already has a stronghold in their brains," she said. "In the lab, however, we can see the first steps, at the very place where the drugs could be the most effective. This could be a strong model for fighting Parkinson's and other diseases that involve neurotoxic aggregation."

Lapidus' lab uses lasers to study the speed of protein reconfiguration before aggregation, a technique Lapidus pioneered. Proteins are chains of amino acids that do most of the work in cells. Scientists understand protein structure, but they don't know how they are built - a process known as folding.

Lapidus' lab has shed light on the process by correlating the speed at which an unfolded protein changes shape, or reconfigures, with its tendency to clump or bind with other proteins. If reconfiguration is much faster or slower than the speed at which proteins bump into each other, aggregation is slow, but if reconfiguration is the same speed, aggregation is fast. 

Srabasti Acharya, lead author and doctoral candidate in Lapidus' lab, tested the molecule, CLR01, (see structure) which was patented jointly by researchers at the University of Duisburg-Essen (Germany) and UCLA. CLR01 binds to the protein and prevents aggregation by speeding up reconfiguration. It's like a claw that attaches to the amino acid lysine, which is part of the protein.

This work was preceded by Lapidus' research involving the spice curcumin. While the spice molecules put the researchers on a solid path, the molecules weren't viable drug candidates because they cannot cross the blood-brain barrier, or BBB, the filter that controls what chemicals reach the brain.

MSU research pushes promising molecule toward clinical trials for treatment of neurological disorders

MSU research pushes promising molecule toward clinical trials for treatment of neurological disorders

Research at Michigan State University, published in the Journal of Biological Chemistry, shows that a small "molecular tweezer" keeps proteins from clumping, or aggregating, the first step of neurological disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease.

The results are pushing the promising molecule toward clinical trials and actually becoming a new drug, said Lisa Lapidus, MSU associate professor of physics and astronomy and co-author of the paper.

"By the time patients show symptoms and go to a doctor, aggregation already has a stronghold in their brains," she said. "In the lab, however, we can see the first steps, at the very place where the drugs could be the most effective. This could be a strong model for fighting Parkinson's and other diseases that involve neurotoxic aggregation."

Lapidus' lab uses lasers to study the speed of protein reconfiguration before aggregation, a technique Lapidus pioneered. Proteins are chains of amino acids that do most of the work in cells. Scientists understand protein structure, but they don't know how they are built - a process known as folding.

Lapidus' lab has shed light on the process by correlating the speed at which an unfolded protein changes shape, or reconfigures, with its tendency to clump or bind with other proteins. If reconfiguration is much faster or slower than the speed at which proteins bump into each other, aggregation is slow, but if reconfiguration is the same speed, aggregation is fast. 

Srabasti Acharya, lead author and doctoral candidate in Lapidus' lab, tested the molecule, CLR01, (see structure) which was patented jointly by researchers at the University of Duisburg-Essen (Germany) and UCLA. CLR01 binds to the protein and prevents aggregation by speeding up reconfiguration. It's like a claw that attaches to the amino acid lysine, which is part of the protein.

This work was preceded by Lapidus' research involving the spice curcumin. While the spice molecules put the researchers on a solid path, the molecules weren't viable drug candidates because they cannot cross the blood-brain barrier, or BBB, the filter that controls what chemicals reach the brain.

MSU research pushes promising molecule toward clinical trials for treatment of neurological disorders

Penn study clarifies action of potential new class of pain relievers that may benefit and not hurt heart

Penn study clarifies action of potential new class of pain relievers that may benefit and not hurt heart

Cancer drugs block dementia-linked brain inflammation, study finds

A class of drugs developed to treat immune-related conditions and cancer -- including one currently in clinical trials for glioblastoma and other tumors -- eliminates neural inflammation associated with dementia-linked diseases and brain injuries, according to UC Irvine researchers.

In their study, assistant professor of neurobiology & behavior Kim Green and colleagues discovered that the drugs, which can be delivered orally, eradicated microglia, the primary immune cells of the brain. These cells exacerbate many neural diseases, including Alzheimer's and Parkinson's, as well as brain injury.

"Because microglia are implicated in most brain disorders, we feel we've found a novel and broadly applicable therapeutic approach," Green said. "This study presents a new way to not just modulate inflammation in the brain but eliminate it completely, making this a breakthrough option for a range of neuroinflammatory diseases."

The researchers focused on the impact of a class of drugs called CSF1R inhibitors on microglial function. In mouse models, they learned that inhibition led to the removal of virtually all microglia from the adult central nervous system with no ill effects or deficits in behavior or cognition. Because these cells contribute to most brain diseases -- and can harm or kill neurons -- the ability to eradicate them is a powerful advance in the treatment of neuroinflammation-linked disorders.

Green said his group tested several selective CSF1R inhibitors that are under investigation as cancer treatments and immune system modulators. Of these compounds, they found the most effective to be a drug called PLX3397, created by Plexxikon Inc., a Berkeley, Calif.-based biotechnology company and member of the Daiichi Sankyo Group. PLX3397 is currently being evaluated in phase one and two clinical trials for multiple cancers, including glioblastoma, melanoma, breast cancer and leukemia.

Crucially, microglial elimination lasted only as long as treatment continued. Withdrawal of inhibitors produced a rapid repopulation of cells that then grew into new microglia, said Green, who's a member of UC Irvine's Institute for Memory Impairments and Neurological Disorders.

Ref : http://www.cell.com/neuron/abstract/S0896-6273(14)00171-8

Multitarget TB drug could treat other diseases, evade resistance -- ScienceDaily

A drug under clinical trials to treat tuberculosis could be the basis for a class  of broad-spectrum drugs that act against various bacteria, fungal infections and parasites, yet evade resistance, according to a study. The team determined the different ways the drug SQ109 attacks the tuberculosis bacterium, how the drug can be tweaked to target other pathogens from yeast to malaria  and how targeting multiple pathways reduces the probability of pathogens becoming resistant.

Led by U. of I. chemistry professor Eric Oldfield, the team determined the different ways the drug SQ109 attacks the tuberculosis bacterium, how the drug  can be tweaked to target other pathogens from yeast to malaria -- and how targeting multiple pathways reduces the probability of pathogens becoming resistant. SQ109 is made by Sequella Inc., a pharmaceutical company. 

"Drug resistance is a major public health threat," Oldfield said. "We have to make new antibiotics, and we have to find ways to get around the resistance problem. And one way to do that is with multitarget drugs. Resistance in many cases arises because there's a specific mutation in the target protein so the drug will no longer bind. Thus, one possible route to attacking the drug resistance problem will be to devise drugs that don't have just one target, but
two or three targets."

Oldfield read published reports about SQ109 and realized that the drug would likely be multifunctional because it had chemical features similar to those found in other systems he had investigated. The original developers had identified one key action against tuberculosis -- blocking a protein involved in building the cell wall of the bacterium -- but conceded that the drug could have other actions within the cell as well since it was found to kill other bacteria and
fungi that lacked the target protein. Oldfield believed he could identify those actions  and perhaps improve upon SQ109. 

"I was reading Science magazine one day and saw this molecule, SQ109, and I thought, that looks a bit like molecules we've been studying that have multiple targets," Oldfield said. "Given its chemical structure, we thought that some of the enzymes that we study as cancer and antiparasitic drug targets also could be SQ109 targets. We hoped that we could make some analogs that would be more potent against tuberculosis, and maybe even against parasites.

More : http://pubs.acs.org/doi/abs/10.1021/jm500131s

Multitarget TB drug could treat other diseases, evade resistance

Hepatitis C treatment cures over 90 percent of patients with cirrhosis...

Tweelve weeks of an investigational oral therapy cured hepatitis C infection in more than 90 percent of patients with liver cirrhosis and was well tolerated by these patients, according to an international study that included researchers from UT Medicine San Antonio and the Texas Liver Institute. Historically, hepatitis C cure rates in patients with cirrhosis (liver scarring) have been lower than 50 percent and the treatment was not safe for many of these patients.

Hepatitis C treatment cures over 90 percent of patients with cirrhosis  

New molecules working against Alzheimer's discovered -- ScienceDaily

New molecules working against Alzheimer's discovered  

Researchers of the Unit of Medicine Design and Molecular Topology (Department of Physics Chemistry) of the University of Valencia (UV) have discovered eight new active molecules against Alzheimer by a novel mechanism of action, different to the currently used medicines. The work has just been published in PLoS One.

Doxorubicin alone or with ifosfamide for treating soft tissue sarcoma? -- ScienceDaily

IN CONTINUATION OF MY UPDATE ON DOXORUBICIN

Dr. Ian Judson of the Royal Marsden Hospital in London and coordinator of this study says, "Our clinical trial was designed to compare combination treatment with doxorubicin and ifosfamide to treatment with doxorubicin alone, and our results show that the combination chemotherapy did not improve overall survival. So, if the goal of treatment is to control the disease, then administering doxorubicin alone is appropriate. On the other hand, if the goal is to shrink the tumor before another intervention or to relieve symptoms, then combination treatment is justifiable. The observed lack of improvement in overall survival points to the need for better treatments for patients with this disease."

For some thirty years, patients with soft tissue sarcomas have been treated with doxorubicin and ifosfamide, but few studies have directly assessed whether doxorubicin should be administered alone or in combination with ifosfamide. EORTC trial 62012 assessed whether the addition of ifosfamide to doxorubicin improves survival of patients with advanced soft-tissue sarcoma compared with doxorubicin alone.

Doxorubicin alone or with ifosfamide for treating soft tissue sarcoma?  

Small peptides as potential antibiotics -- ScienceDaily

Small peptides as potential antibiotics 

Eating fruits, vegetables linked to healthier arteries later in life

Women who reported consuming the most fruits and vegetables (eight to nine servings a day for a 2,000-calorie diet) in their 20s were 40 percent less likely to have calcified plaque in their arteries in their 40s compared with those who ate the least amount (three to four servings a day) during the same time period. This association persisted even after researchers accounted for other lifestyle behaviors, as well as for their current-day diets, further demonstrating the role dietary patterns at younger ages may play. 

"These findings confirm the concept that plaque development is a lifelong process, and that process can be slowed down with a healthy diet at a young age," Miedema said. "This is often when dietary habits are established, so there is value in knowing how the choices we make in early life have lifelong benefits."

Surprisingly, the same benefit did not hold true for men, which warrants further investigation.

"Several other studies have also suggested that a diet high in fruits and vegetables is less protective in men, but we do not have a good biological reason for this lack of association," Miedema said, adding that the study had less power to evaluate men (62.7 percent were female vs. 37.3 percent male).

The study included 2,508 participants from the ongoing government-sponsored Coronary Artery Risk Development in Young Adults (CARDIA) study, which is evaluating how heart disease develops throughout adulthood. CARDIA began in the mid-1980s with a group of men and women 18-30 years of age and has collected extensive data on medical, socioeconomic, psychosocial and behavioral characteristics.

Eating fruits, vegetables linked to healthier arteries later in life  

Oral cancer drug improves outcomes in women with resistant gynecologic cancers

PARP inhibitors prevent cancer cells from repairing themselves after experiencing DNA damage (for example from chemotherapy or radiation). Research has previously shown that veliparib is effective in combination with chemotherapy, but little data was available to indicate whether veliparib was effective as a single agent. Results of this multicenter trial suggest that it is.

"One criticism of the PARP drugs is they are not active in patients who have developed resistance to other therapies, but we found veliparib appears to be effective in some platinum-resistant patients with recurrent or persistent disease," said Robert L. Coleman, MD, lead author of the study and professor and vice chair of clinical research at the University of Texas MD Anderson Cancer Center, Houston. "Most of these patients have run out of treatment options, and it is very hopeful to potentially have another therapy to offer them."

In the study, 50 patients with BRCA gene mutations treated at one of 18 centers took veliparib by mouth twice a day. The median number of monthly treatment cycles was six (ranging from one to 22). Overall, 13 patients (26 percent) responded positively to the therapy, meaning the tumors shrank in size, including two patients in whom the tumors disappeared completely. In addition, disease was stabilized for more than four months in nearly half of the women (24).

"Patient recruitment can be a problem for many clinical trials, however, this one filled up very quickly, which reflects that women and their doctors understand that PARP inhibitors hold real promise," said Dr. Coleman.

Oral cancer drug improves outcomes in women with resistant gynecologic cancers