Bio Screening Industry News

Research into Alzheimer’s disease seems an unlikely approach to yield a better way to fight urinary tract infections (UTIs), but that’s what scientists at Washington University School of Medicine in St. Louis and elsewhere recently reported.

One element links the disparate areas of research: amyloids, which are fibrous, sticky protein aggregates. Some infectious bacteria use amyloids to attach to host cells and to build biofilms, which are bacterial communities bound together in a film that helps resist antibiotics and immune attacks. Amyloids also form in the nervous system in Alzheimer’s disease, Parkinson’s disease and many other neurodegenerative disorders.

To probe amyloids’ contributions to neurodegenerative diseases, scientists altered potential UTI-fighting compounds originally selected for their ability to block bacteria’s ability to make amyloids and form biofilms. But when they brought the compounds back to UTI research after the neurology studies, they found the changes had also unexpectedly made them more effective UTI treatments.

“Thanks to this research, we have evidence for the first time that we may be able to use a single compound to impair both the bacteria’s ability to start infections and their ability to defend themselves in biofilms,” says senior author Scott J. Hultgren, Ph.D., the Helen L. Stoever Professor of Molecular Microbiology at Washington University.

The findings were reported online in Nature Chemical Biology.

The National Institutes of Health has estimated that over 80 percent of microbial infections are caused by bacteria growing in a biofilm, according to Hultgren. Scientists in Hultgren’s laboratory have worked for decades to understand the links between biofilms and UTIs.

“UTIs occur mainly in women and cause around $1.6 billion in medical expenses every year in the United States,” says co-lead author Jerome S. Pinkner, laboratory manager for Hultgren. “We think it’s likely that women who are troubled by recurrent bouts of UTIs are actually being plagued by a single persistent infection that hides in biofilms to elude treatment.”

Co-lead author Matthew R. Chapman, Ph.D., now associate professor of molecular, cellular and developmental biology at the University of Michigan, was a postdoctoral fellow in Hultgren’s lab in 2002 when he discovered that the same bacterium that causes most UTIs, Escherichia coli, deliberately makes amyloids. The amyloids go into fibers known as curli that are extruded by the bacteria to strengthen the structures of biofilms.

To treat UTIs, Hultgren’s lab has been working with Fredrik Almqvist, Ph.D., a chemist at the University of Umea in Sweden, to develop compounds that block bacteria’s ability to make curli, disrupting their ability to make biofilms and leaving them more vulnerable to antibiotics or immune system attacks. Almqvist recently suggested altering a group of the most promising curli-blockers to see if they could also block the processes that form amyloids in Alzheimer’s disease.

The alterations worked: In laboratory tests, the new compounds prevented the protein fragment known as amyloid beta from aggregating into amyloid plaques like those found in the brain in Alzheimer’s disease. When scientists took the new compounds back to a mouse model of UTIs, though, they received a surprise. The altered compounds were better at reducing the virulence of infections, inhibiting not only curli formation but also the formation of a second type of bacterial fibers, the pili.

“Pili aren’t made of amyloids, but they are essential to both biofilms and to the bacteria’s ability to initiate an infection,” Hultgren says.

Hultgren and colleagues are already developing even more potent infection and amyloid fighters, screening a library of thousands of chemicals similar to the most promising compounds from the study.

Chapman cautions that it’s too early to tell which, if any, of the compounds will be helpful in treating neurodegenerative diseases.

“Much neurodegenerative drug development has focused on ways to break up amyloids or prevent them from forming, but because amyloids may also be an important part of normal cellular physiology, we need to identify molecules that will target only the toxic amyloid state,” he says.

Cegelski L, Pinkner JS, Hammer ND, Cusumano CK, Hung CS, Chorell E, Aberg V, Walker JN, Seed PC, Almqvist F, Chapman MR, Hultgren SJ. Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation. Nature Chemical Biology, published online.

Funding from the Swedish Natural Science Research Council, the Knut and Alice Wallenberg Foundation, the National Institutes of Health and the Burroughs Wellcome Fund supported this research.

Source
Washington University in St. Louis

A study carried out by the scientists at the Scripps Research Institute illustrated a novel, highly practical strategy for identifying molecules that avert a particular form of immune cells from launching assaults on their host. These findings have added a potent new-fangled tool to the ongoing investigation for probable treatments for autoimmune diseases like MS or multiple sclerosis

, as well as for the treatment of types of leukemia like myeloid leukemia.

The study conducted by Thomas Kodadek, a professor in the Chemistry and Cancer Biology Departments, Scripps Florida, and associates was printed in the ‘Chemistry & Biology’ Journal.

In the novel study, Kodadek and his associates utilised samples taken from an animal model of MS for screening for T cells – a kind of white blood cell that dons fundamental role in the immune system – with an increasing presence in the ailment. The screen additionally recognized molecules that interfered with such T cells’ auto-reactive nature or their assault on the body itself instead of a foreign intruder like a virus or bacteria.

Kodadek stated that their method concurrently unearths and separates auto-reactive T cells along with inhibitors to them. A dual achievement at the core of which is a relative screening procedure of healthy T cells vs. Disease-causative T cells. Even as the process is technically complex and intricate, the thought behind it is not. The scientists intended to make the process of recognizing compounds simpler that could hinder auto-reactive T cells with outstanding specificity and the scientists were able to accomplish their objective.

The scientists employed a model of MS – an autoimmune inflammatory condition that affects the brain and the spinal cord for the study. MS is a condition wherein the immune system assaults the myelin sheath coating and defensive nerve cells that lead to a host of symptoms dependent on what component of the nervous system has been affected. Prevalent signs of the condition involve weariness, numbing sensation; difficulties experienced in walking balancing and co-ordination; dysfunctional bladder and bowel; ocular problems; giddiness and vertigo; sexual dysfunction problems; pain, mental problems; emotional variations and spastic behaviours.

Simplification of the Process

Kodadek and his associates set up the novel method for shedding light on these autoimmune diseases and other kinds of disorders and produced a vast assortment of peptoids –molecules linked to, though more constant as compared to the peptides which made up the proteins. By organizing thousands of the peptides microscopically, the prototype of binding antibodies (a form of autoimmune molecule) and peptoids could be pictured. By observing samples drawn from animal models of an identified disease such as MS, peptoids which exhibited binding to antibodies closely linked with that disease could be easily identified.

Even better, peptoids which showed binding to the autoreactive T cells could be spotted with no awareness of the particular antigen (molecules that elicit the immune assault), offering an impartial approach with which to explore potentially beneficial compounds.

Kodadek stated that they had made a breakthrough where they set up a system that identifies T cell receptors which are copious in an ailing animal and in sapped levels in a healthy animal.

Potential for Curative Breakthrough

The novel process created a novel potential for curative finding. Molecules that targeted auto-reactive T cells in a direct way, while overlooking those T cells that identify foreign antigens, could provide the basis for a new drug development program intended at elimination of autoreactive cells with no affect on the normal functioning of the immune system.

Kodadek stated that the novel study is not the ultimate solution as it employed a model of MS elicited by a sole antigen whereas in human beings there could be 2 to even more antigens that trigger an autoimmune disease like MS that needs further investigation. The method could be applicable with ease to blood cancers, although as the disease-causative T cells have been completely characterized and there being quite a few of them.

Source: simplehealthguide.com

HOUSTON — (December 9, 2009) — On rare occasions, an infant is born with outward appearance of a female but the XY chromosomes of a male. If the child has a normal Y chromosome — the chromosome responsible for testicular development — the condition is known as androgen insensitivity syndrome.

Experts estimate such births occur in about one in 20,000 infants. Other children are born with a partial form of the condition that can affect their genitalia and/or fertility, but how many is not known.

The cause is a wide range of androgen receptor (AR) mutations that fail to perceive the presence of the male hormones testosterone and dihydrotestosterone to differing degrees. How to overcome the problem remained a mystery until Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center experts used a high throughput, automated microscopy technique called high content analysis to solve the puzzle. A report of their findings appears in the current issue of PLoS One, an open access journal.

Reverse effect of mutation

They not only identified the functional abnormality of the AR, but also used high content analysis to “personalize” a treatment that reverses the effects of that mutation.

“With this microscopy technique, we have been able to quantify how the receptor moves and functions inside cells taken from children with normal receptors and in those with the mutation,” said Dr. Marco Marcelli, professor of medicine-endocrinology at BCM and a physician at the Michael E. DeBakey Veterans Affairs Medical Center. He and Dr. Michael Mancini, associate professor of molecular and cellular biology at BCM, and director of its Integrated Microscopy Core, are senior authors of the report.

Androgen insensitivity syndrome

They used banked cells taken from patients – both those with the mutation and those without – to study the action of the receptor in cell cultures grown in the laboratory. Dr. Michael J. McPhaul, a collaborator on the study and a professor of internal medicine—endocrinology at The University of Texas Southwestern School of Medicine Dallas, provided the samples from patients with androgen insensitivity syndrome.

“We did this on a cell-by-cell basis, using high content analysis,” said Mancini. “It is a proof-of-principle study carried out as though we had a patient and a library of hormones. We tried to find the perfect hormone for the mutation through high-speed collection of dozens of measurements from thousands of cells.”

“In two of the three specimens we tested, we found we were able to reverse the activity of the mutated receptor to almost normal,” said Marcelli.

In one patient, large doses of the male hormone dihydrotestosterone were sufficient. In another, they used a synthetic androgen that also activated the receptor.

These approaches overcame the central problem – the mutation changes the shape of the receptor and prevents it from maintaining normal contact with the hormone. It is as though a key is bent and can no longer turn the tumblers in a lock. In these cases, the hormone is designed to go into a pocket created by the receptor. When the pocket is changed by the mutation, the hormone is unable to establish good contact.

“Large amounts of testosterone may create more stable contact,” said Marcelli. “The synthetic androgen may have a conformation that establishes better contact.”

Superandrogen

In the future, scientists may be able to screen large banks of such compounds to find a “superandrogen” that may be even more efficient.

“We might be able to use this technique to create a personalized medicine test,” said Mancini.

Similar techniques might be used to screen drugs for treatment of different cancers, particularly those in which the androgen receptor is responsible for cancer progression. This study proves that the concept is valid providing quantitative information collected quickly on numerous measurements normally requiring separate biochemical tests and huge numbers of cells.

Marcelli said they have yet to use this kind of technique in patients, and such studies will require careful preparation, and go through a variety of approvals before it can be used in clinics. He also said it would be used only in individuals with the partial form of the syndrome. Finding well-matched hormones to defective androgen receptors through screening of thousands of compounds from available libraries could be one of the future developments of this technique.

The paper’s first author, Dr. Adam T. Szafran, an M.D./Ph.D. student who worked in Mancini’s laboratory, championed these studies, said Mancini. Szafran is now finishing the clinical part of his studies at BCM.

Others who took part in this study include Drs. Sean Hartig and Ivan P. Uray, Maria Szwarc, Jennifer Bell, Huiying Sun, Yuqing Shen and Sanjay N. Mediwala, all of BCM. Sun, Shen and Mediwala are also of the MEDVAMC.

Funding for this work came from the National Institute of Diabetes and Digestive and Kidney Diseases, the John S. Dunn Foundation and the Veterans Administration.

Source: bcm.edu

Computer compatibility tests might help flu-fighting drugs find their groove.

A pandemic of the H1N1 swine flu virus has health officials worried that the virus could develop resistance to drugs such as Tamiflu used to treat infected people. A new computerized screening method could help find new or already existing drugs that find a flu virus’ weak spot, researchers from the University of California, San Diego reported December 6 at the annual meeting of the American Society for Cell Biology.

Researchers Daniel Dadon, Jacob Durrant and J. Andrew McCammon, all of UCSD, made a computer movie of slight structural shifts occurring in the neuraminidase 1 enzyme (the N1 in H1N1 and H5N1), a protein found in the avian and swine influenza viruses. Those changes reveal possible target areas that could allow drugs to circumvent a virus’ usual means of becoming resistant.

All influenza viruses have a neuraminidase enzyme, but the protein comes in several subtypes. Previous work had shown that the N1 subtype contains a loop that makes it more flexible than other neuraminidase subtypes, says Rommie Amaro, a computational biologist at the University of California, Irvine. “It is particularly nimble,” she says. The enzyme’s flexibility could affect the way drugs bind to it.

Enlarge

Antiviral drugs can wedge into a cavity within an active site of the N1 neuraminidase enzyme (blue) and stop the enzyme’s action. Mutations in the enzyme (colored dots) can reduce the efficiency with which antiviral drugs such as Tamiflu bind, creating drug-resistant forms of the virus. Newly discovered drugs (green) lodge in the enzyme’s active site in a different location, possibly being able to knock out viruses that have become resistant to other drugs.Daniel Dadon and Jacob Durrant, University of California, San Diego

Analyses of still frames from the simulation, which is called a relaxed complex scheme, revealed 27 different natural conformations that the N1 protein could take on under conditions it might encounter in a host cell. Some parts of the protein change shape readily and some stiffer portions are locked into place, the researchers discovered.

Drugs currently used against flu — including oseltamivir, better known as Tamiflu, peramivir and zanamivir — all insert themselves into neuraminidase at about the same location within that enzyme. When the drugs insert into that pocket, they block the enzyme’s ability to release newly made viral particles from the cell, and this blockage prevents the spread of the disease.

That location is prone to structural changes such as those revealed by the simulation, and to genetic changes that affect the amino acid building blocks that compose the protein. Many of those amino acid changes also alter the shape of the pocket, keeping the drugs from binding and thus making the flu virus resistant to the drugs.

To find drugs that could block the protein’s active site in a different way — and knock out viruses resistant to the currently used drugs — the researchers mined a library of FDA-approved drugs. The team digitally sliced up the drugs and simulated how the drug fragments might bind to all of the enzyme’s forms.

Among those fragments, the team found 15 novel compounds that could wedge into the protein’s pocket and block its action better than Tamiflu or other antiviral drugs would. A closer examination revealed that those 15 compounds share a common structure. What’s more, the compounds lodge into a part of the protein that doesn’t allow changes easily, meaning that those areas are less likely to mutate and develop drug resistance than the parts of the protein that come into contact with Tamiflu and other current flu treatments, Dadon says.

But because the computer-generated fragment molecules don’t exist in the real world, the researchers needed to see whether any existing, small molecules could work just as well. Searching four databases of drugs turned up six small molecules that had the same common structure as the digitally diced compounds. These real compounds are currently being tested by collaborators in Australia to determine whether they really do block the flu’s action.

Both of the approaches Dadon’s team followed in the new drug design scheme — examining all forms of the protein and then screening a library of fragments from approved drugs — could be easily adapted for other molecules, Amaro says. The caveat is that researchers need to have prior knowledge of an enzyme’s structure in order to develop effective drugs, she says.

Source; Sciencenews.org

Walter and Eliza Hall Institute scientist Dr Guillaume Lessene has won this year’s Biota Award for Medicinal Chemistry, awarded by the Royal Australian Chemical Institute.

Dr Lessene, who runs a laboratory in the institute’s Structural Biology Division, won the award for his role in the discovery of several compounds that interact with a protein that has been implicated in the poor response of many cancers to anti-cancer treatments.

The protein is a member of the Bcl-2 family of proteins. This protein family has a role in tumour development, anti-cancer-drug resistance and cancer spread. Dr Lessene’s drug target, in particular, is thought to be involved in the drug resistance of many tumours.

The Biota Award is presented annually to the chemist judged to be responsible for the best drug design and development paper published, patent taken out, or commercial-in-confidence report concerning small molecules as potential therapeutic agents.

Together with eight co-inventors Dr Lessene has made a patent application that describes how his compounds could be used to restore the cell death process that is important in combating the growth of cancers.

Since 2001 Dr Lessene has focused his research on developing small molecules that inhibit the Bcl-2 family of proteins.

“It is expected that drugs targeting Bcl-2-like proteins will have a major impact in cancer treatment,” he said.

Usually, when a cell’s DNA is damaged the cell tries to repair itself and, if it can’t, undergoes a process of programmed cell death.

Cancer develops when, despite cells having DNA damage, they don’t die but continue to divide, leading to tumour formation. This happens when the signal that tells the cell to die is inhibited by Bcl-2 proteins, which allows the cell to keep dividing.

Through high throughput screening, medicinal chemistry, and structure-guided drug design, Dr Lessene and the institute’s drug discovery team have been identifying and refining compounds that inhibit the Bcl-2 proteins.

“From a drug discovery point of view the Bcl-2 proteins are challenging targets because of the size and shape of their binding sites,” Dr Lessene said. “Our successful work therefore represents a considerable achievement, particularly in the field of protein-protein interactions.”

The research leading to the discovery of these compounds is the basis of a collaboration and licensing agreement between the Walter and Eliza Hall Institute, Genentech Inc and Abbott, the leader in Bcl-2 inhibitor development.

Dr Lessene is the second person from the Walter and Eliza Hall Institute to win the Biota Award. Dr Jonathan Baell, also from the Structural Biology Division, received the award in 2004.

Source: Walter and Eliza Hall Institute

One element links the disparate areas of research: amyloids, which are fibrous, sticky protein aggregates. Some infectious bacteria use amyloids to attach to host cells and to build biofilms, which are bacterial communities bound together in a film that helps resist antibiotics and immune attacks.

Amyloids also form in the nervous system in Alzheimer’s disease, Parkinson’s disease and many other neurodegenerative disorders.

To probe amyloids’ contributions to neurodegenerative diseases, scientists altered potential UTI-fighting compounds originally selected for their ability to block bacteria’s ability to make amyloids and form biofilms. But when they brought the compounds back to UTI research after the neurology studies, they found the changes had also unexpectedly made them more effective UTI treatments.

“Thanks to this research, we have evidence for the first time that we may be able to use a single compound to impair both the bacteria’s ability to start infections and their ability to defend themselves in biofilms,” said senior author Scott J. Hultgren, Ph.D., the Helen L. Stoever Professor of Molecular Microbiology at Washington University.

The findings were reported online in Nature Chemical Biology.

The National Institutes of Health has estimated that over 80 percent of microbial infections are caused by bacteria growing in a biofilm, according to Hultgren. Scientists in Hultgren’s laboratory have worked for decades to understand the links between biofilms and UTIs.

“UTIs occur mainly in women and cause around $1.6 billion in medical expenses every year in the United States,” said co-lead author Jerome S. Pinkner, laboratory manager for Hultgren.

“We think it’s likely that women who are troubled by recurrent bouts of UTIs are actually being plagued by a single persistent infection that hides in biofilms to elude treatment,” Pinkner added.

Co-lead author Matthew R. Chapman, Ph.D., now associate professor of molecular, cellular and developmental biology at the University of Michigan, was a postdoctoral fellow in Hultgren’s lab in 2002 when he discovered that the same bacterium that causes most UTIs, Escherichia coli, deliberately makes amyloids. The amyloids go into fibers known as curli that are extruded by the bacteria to strengthen the structures of biofilms.

To treat UTIs, Hultgren’s lab has been working with Fredrik Almqvist, Ph.D., a chemist at the University of Umea in Sweden, to develop compounds that block bacteria’s ability to make curli, disrupting their ability to make biofilms and leaving them more vulnerable to antibiotics or immune system attacks.

Almqvist recently suggested altering a group of the most promising curli-blockers to see if they could also block the processes that form amyloids in Alzheimer’s disease.

The alterations worked: In laboratory tests, the new compounds prevented the protein fragment known as amyloid beta from aggregating into amyloid plaques like those found in the brain in Alzheimer’s disease.

When scientists took the new compounds back to a mouse model of UTIs, though, they received a surprise. The altered compounds were better at reducing the virulence of infections, inhibiting not only curli formation but also the formation of a second type of bacterial fibers, the pili.

“Pili aren’t made of amyloids, but they are essential to both biofilms and to the bacteria’s ability to initiate an infection,” Hultgren said.

Hultgren and colleagues are already developing even more potent infection and amyloid fighters, screening a library of thousands of chemicals similar to the most promising compounds from the study.

Chapman cautions that it’s too early to tell which, if any, of the compounds will be helpful in treating neurodegenerative diseases.

“Much neurodegenerative drug development has focused on ways to break up amyloids or prevent them from forming, but because amyloids may also be an important part of normal cellular physiology, we need to identify molecules that will target only the toxic amyloid state,” he said.

Source: farsnews.com

iThemba Pharmaceuticals’ service division and Pyxis Discovery announced today that they have signed a collaborative agreement to jointly market both companies’ services.
Pyxis’s world class computational chemistry and lead discovery expertise will be coupled with iThemba’s service division to provide medicinal and synthetic chemistry support to projects identified through Pyxis’ international client network. iThemba Pharmaceuticals and Pyxis Discovery also announced today that they are entering into a co-marketing agreement to offer virtual libraries which will be exclusively synthesized for clients. Pyxis’s smart approach of designing and selecting compounds facilitates a rapid and efficient lead discovery and library design process and this coupled to iThemba’s expertise in synthetic and medicinal chemistry will provide our customers with a unique service offering opportunity.
“The intellectual and technological support from Pyxis will enhance both of our service offerings,” said Chris Edlin, CSO of iThemba. “Our customers will gain the advantage of our coupled expertise in design, synthesis and medicinal chemistry prowess.”
“Combining the outstanding medicinal chemistry expertise of iThemba with our design approach helps us to provide our clients with a more complete set of services, resulting in swiftly progressing lead discovery and optimization projects.” said Ron van der Valk, Managing Director of Pyxis Discovery. “In addition to this, we hope that our collaboration with iThemba will support their ambition to bring affordable medicines to the less fortunate people in this world.”
About iThemba Pharmaceutical (Pty) Ltd. (http://www.ithembapharma.com)
iThemba Pharmaceuticals (Pty) Ltd., based in Modderfontein, Gauteng, South Africa is founded to discover and develop new and affordable medicines for the diseases of poverty in Africa. The company is funded by the Biotechnology Regional Innovation Centers, LIFElab and BioPAD of the Department of Science and Technology, Government of South Africa. Utilizing leading edge proprietary technology and its expertise in synthetic organic chemistry, iThemba Pharmaceuticals will become the premier research focal point in Africa for infectious diseases including HIV, tuberculosis, malaria and their associated co-infections. The company will create shareholder value by coupling the company’s own drug discovery efforts with collaborative research initiatives and cash-generating contracts to reduce the risks and costs of developing medicines for neglected diseases and low profit-margin markets.
About Pyxis Discovery B.V. (http://www.pyxis-discovery.com)
The ambition of Pyxis Discovery is to be the preferred chemistry service provider for companies that are active in small molecule drug discovery. Pyxis Discovery’s Smart approach of designing and selecting compound libraries facilitates a rapid and efficient lead discovery process, yielding lead compounds with excellent pharmacological profiles. Pyxis Discovery uses proprietary software algorithms for compound design and selection and a Global Supplier Database of nearly all commercially available screening compounds to provide its clients with screening libraries that are tailored to their specific needs. Furthermore, Pyxis Discovery offers high quality compound libraries off the shelf. Pyxis Discovery is headquartered in the Netherlands and has a worldwide presence with also an office in Boston, Massachusetts and representation in Japan.
Source: Pyxis Discovery B.V.

Source: melodika.net

The Drugs for Neglected Diseases initiative (DNDi) has announced an agreement with drug giant Pfizer that will allow it access to the Pfizer library of novel chemical entities, in order to screen it for compounds that could be developed into new treatments for three of the most neglected infectious diseases of poverty: human African trypanosomiasis (HAT), visceral leishmaniasis (VL) and Chagas disease.

Pfizer vice president Dr Manos Perros said, “We are expanding our commitment to the fight against tropical diseases by joining forces with DNDi by sharing our collection of chemical compounds and the knowledge and expertise associated with these chemical entities”. His colleague Dr Sam Azoulay said, “We are confident that the significant resources and expertise that public-private partnerships such as this one bring together, will accelerate and significantly increase the chances of success in the search for effective new drugs against serious infections that disproportionately affect the poor”.

Under the agreement, scientists in institutes affiliated with DNDi will test at least 150,000 compounds in the Pfizer library against Trypanosoma brucei, Leishmania donovani and Trypanosoma cruzi, the kinetoplastid parasites that cause HAT, VL and Chagas disease, respectively. The researchers will seek compounds that show initial activity against the parasites, and thus might form the basis for novel drug discovery programmes to treat the diseases. The screening will be undertaken at the Eskitis Institute for Cell and Molecular Therapies, Griffith University in Brisbane, Australia (for HAT) and the Institut Pasteur Korea (VL and Chagas disease).

“This agreement provides us access to a compound library of novel chemical entities that has never been explored for kinetoplastid diseases. This marks an important step towards DNDi’s objective of building a robust portfolio and to feed the research and development pipeline with new promising compounds,” said Dr Shing Chang, R&D director at DNDi. In July this year, DNDi announced a similar agreement with Merck – see press release.

Within the same week as the finalising of its agreement with Pfizer, DNDi also announced it is to receive $15 million of Gates Foundation funding over the next five years, which it will use for the development of fexinidazole, currently the only new drug candidate in clinical development for sleeping sickness – see press release. Further information about DNDi is available here.

Source: tropika.net

Contacts: Patty Mattern, University News Service, (612) 624-2801, mattern@umn.edu
John Merritt, Office of the Vice President for Research, (612) 624-2609
Stacie Byars, Celladon, (206) 660-2588

MINNEAPOLIS / ST. PAUL (11/23/2009) —Research conducted by University of Minnesota scientists, in collaboration with Celladon Corporation, has led to the invention of technology to more rapidly identify compounds for the treatment of heart failure.

Chronic heart failure is an increasingly important health problem. It is the leading medical cause of hospitalization and is expected to result in an estimated direct and indirect cost to the health care system of $37.2 billion in 2009 alone. About 5.7 million people in the United States have heart failure, and it contributes to or causes some 290,000 deaths annually. However, developing new treatments is an extremely costly and time-consuming process, taking nearly a decade to gain regulatory approval and requiring hundreds of millions of dollars.

The technology, developed by the universitys David Thomas and Razvan Cornea and Celladon Corporations  Krisztina Zsebo, allows for increased screening efficiency of compounds capable of disrupting the interactions of proteins implicated in the development of heart failure. Fluorescence resonance energy transfer (FRET) is used to measure disruption of the calcium regulatory system, which has long been implicated in cardiovascular disease. This will provide key information on a particular drugs likelihood of success early in the screening process, since compounds that decrease FRET are good candidates for further development.

“Dr. Cornea and I, along with our students, have worked for more than a decade developing methods for preparing membranes from purified components, and using FRET to detect changes in protein interactions,” Thomas said. “Scientists from Celladon saw the potential for drug discovery, and this resulted in a breakthrough that has added an exciting new dimension to our research program.”

The high-throughput assay, developed by the university team, is based on a reconstituted membrane system composed of purified lipid and protein components. This technique is especially important because the interactions of integral membrane proteins are more complex than soluble proteins, making it very difficult to produce a synthetic system that recapitulates the cellular interactions in a large-scale and reproducible manner.

Celladon, based in La Jolla, Calif., has acquired an exclusive license for the technology from the University of Minnesota for the development of molecular therapies for cardiovascular diseases. Celladon also provided funding for the research that allowed Thomas to further refine the assay.

“This technology is very important to the efficient selection and advancement of compounds with the potential to increase cardiac contractility and potentially accelerates product opportunities that will ultimately benefit patients and development partners alike,” said Krisztina M. Zsebo, Ph.D., president and chief executive officer of Celladon Corporation. “Celladon’s investigation and development of first-in-class CDN small molecules as intravenous and oral drugs for the treatment of acute and chronic heart failure sets us apart in the cardiovascular field and presents multiple partnering opportunities.”

Source: umn.edu

In 2004, Avi Kremer, a 29-year old Harvard Business School student, was diagnosed with ALS. Avi’s doctors told him there was nothing that modern medicine could do for him. In response, he and fellow students founded Prize4Life, Inc. , a non-profit organization dedicated to accelerating research for treating and curing ALS by using the leverage of large inducement prizes. In 2006, Prize4Life opened the “ALS Biomarker Challenge,” offering a $1 million prize to a researcher who could find a biomarker that would reliably measure disease progress in ALS patients. A year ago, it established the “Avi Kremer ALS Treatment Prize,” a $1 million award for finding a treatment candidate that reliably and significantly increases the lifespan of ALS mouse models. Competing teams are actively pursuing several approaches, including therapies to replace damaged cells, protein-based therapeutics, and small molecule drugs that interfere with ALS-implicated pathways. Competition for both prizes is open to all interested researchers. Both prizes have attracted research teams from industry and academia from around the world.

The SOD1 Mouse

Three percent of ALS cases are associated with mutations in the antioxidant enzyme superoxide dismutase-1 (SOD1) gene, the first gene associated with ALS. With so little known about the genetics of ALS, research so far has concentrated on the pathogenesis of SOD1 mutations in laboratory mice. To provide researchers with the most widely used ALS mouse models available for preclinical drug testing, Prize4Life has partnered with The Jackson Laboratory (JAX). The models, popularly known as SOD1 mice, are distributed from dedicated supply colonies maintained by JAX® Breeding Services. JAX currently distributes 12 different SOD1 models - with different forms of the SOD1 mutation and on different genetic backgrounds. Among the most widely used of these models is JAX® Mice strain B6SJL-Tg(SOD1*G93A)1Gur/J (002726). Like several other SOD1 models, this one has a high copy number of the mutant human superoxide dismutase 1 (SOD1) transgene, which contains the Gly93–>Ala (G93A) substitution. The mutation underlies the most studied form of inherited ALS in humans. The mice lose motor neurons in the spinal cord, become paralyzed in one or more limbs, and die by four to five months. These phenotypes closely model those of human ALS (Gurney et al. 1994). As noted by Dr. Tom Maniatis, Chair of Columbia University’s Biochemistry & Molecular Biophysics Program, a prominent ALS researcher, and a member of Prize4Life’s Scientific Advisory Board, “An effective treatment for ALS is desperately needed, and the existing [SOD1] mouse model is the primary gateway to clinical trials” (CheckOrphan 2009).

SOD1 Mice Need Special Care

Many of the initial studies conducted with Tg(SOD1*G93A)1Gur/J mice have provided a wealth of information and insight on how to best use them in preclinical trials. However, like other highly expressed transgenes, the G93A transgene can spontaneously lose copy number, which can greatly confound experimental results. Therefore, the mice need to be handled carefully. When Prize4Life approached JAX to establish a dedicated supply for their researchers, Dr. Melanie Leitner (Chief Operating Officer and Chief Scientific Officer for Prize4Life), Dr. A. Sheila Menzies (Scientific Program Officer for Prize4Life), and Dr. Cathleen Lutz (Associate Director for Genetic Resource Science at JAX) produced a companion set of informational materials entitled “Working with ALS Mice”. The materials are available at www.jax.org/jaxmice/literature/factsheet/working_with_ALS_mice.pdf.

“Prize4Life spearheaded this effort,” say Lutz. “It’s really targeted to those investigators who are new to the field of ALS and who are working with the SOD1 mice and designing their preclinical trials. The scientific community has learned a great deal about how to work with these mice over the years. It’s important to make that information more widely known so that valuable time and resources aren’t wasted by repeating past mistakes.”

If Prize4life succeeds in its goal of bridging the critical steps between academic discovery and therapy in the clinic, it could have major implications for ALS patients and for any group trying to solve a biomedical problem. Interested researchers can learn more at www.prize4life.org.

References

CheckOrphan. 2009. Prize4Life marks one-year anniversary of Avi Kremer ALS Treatment Prize. http://www.checkorphan.org/news/prize4life_marks_one_year_anniversary_avi_kremer_als_treatment_prize. October 13, 2009.

Gurney ME, Pu H, Chiu AY, Daly Canto MC, et al. 1994. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264:1772-5.

Source: animallab.com