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The NIH Molecular Libraries Program: Identifying Chemical Probes for New Medicines

Last Updated on Saturday, 24 July 2010 04:24 Written by Editor Monday, 12 July 2010 02:12

Alice McCarthy

In 2003, several program leaders within the National Institutes of Health (NIH) recognized that the results from the recently completed Human Genome Project were a launching pad for further study. Now that scientists knew the genome, how could they determine gene function? In particular, how could scientists find specific biological pathways and targets that could lead to new advances in biology and new drug therapies?

MLP was founded to fund research spanning multiple NIH institutes, all with one goal: identify new chemical probes to explore new targets for drug therapies.

The Molecular Libraries Program (MLP), an NIH Roadmap Initiative first funded in 2004, has partially answered those questions. “At the time the term ‘chemical genomics’ was on the minds of NIH researchers,” explains Carson Loomis, Ph.D., Program Director, Molecular Libraries. “The human genome was available and it was agreed that the NIH should become more involved in screening new small molecules to get better targets.” The pharmaceutical industry had become frustrated by drug failures in development lacking the means to sufficiently validate potential targets. “They were at the breaking edge of science, yet when a new kinase was discovered and they developed a drug for it, it would often fail,” explains Loomis. “The feeling was that we needed more basic research and that the NIH needed to further this cause of validating targets.”

The act of Congress creating the MLP now includes the efforts of nine Molecular Libraries Probe Production Centers. They include one intramural NIH site, the National Center for Chemical Genomics (NCGC), and eight extramural sequencing and screening centers: the Broad Institute, the Sanford-Burnham Medical Research Institute, Johns Hopkins University, Scripps Research Institute, the University of New Mexico, Southern Research Institute, the University of Kansas, and Vanderbilt University.

The common purpose of these probe production centers is to generate new small molecule chemical probes by performing high throughput screening, secondary screens, and medicinal chemistry. The biological assays for these probes are sourced from the scientific community at large.

MLP was founded to fund research spanning multiple NIH institutes, all with one goal: identify new chemical probes to explore new targets for drug therapies.

Screening Library

The workhorse of the MLP program is its 350,000-strong library of unique chemical structures of the NIH’s Molecular Libraries Small Molecule Repository (MLSMR). The MLSMR is screened with biological assays or bioactivity experiments looking for particular areas of biological activity.

Small molecule probes can be targeted to interact with extreme precision with a cell or cell byproduct. This specificity provides useful details about the steps in a cell’s function and ultimately to its disease pathway. A “true positive active” compound found to be active against a biological target is classified as a chemical probe.

As part of the MLP mandate, all identified probes are immediately reported to the National Library of Medicine’s PubChem, a chemical and biological activity repository. Full results may be withheld for up to year to allow investigators to publish their findings.

Though only 350,000 of the 26 million unique chemical structures found in PubChem derive from the MLP, they have generated a wealth of information when combined with the biological assays also deposited. Each participating MLP center receives the screening library and uses it to test a variety of biological questions. “The result is that over 90 million unique biological results have been placed in PubChem from the MLP sites, representing over 80% of the total,” explains Steve Bryant, Ph.D., Program Director, PubChem. “It’s the combination of the screening library with the unique bioassays that provide the information that lead to the designation of probe.”

All of the centers deposit the entire screening experiment, even if most of the results showed no activity or low activity. “It’s important to know what doesn’t work as well as what does,” explains Bryant.

Before victory is proclaimed, however, a probe has to be validated. Enrique Michelotti, Ph.D., who oversees this process within the MLP, says, “The assays and the probes identified have to address a very specific problem in biology.” Assay providers need to supply the proposed assay to NIH for peer-review. The network runs the assay through high throughput screening against the 350,000 compound MLSMR collection. “Any new compound that is active in that assay is followed up by chemistry and has to be best in class in that it is addressing some particular issue in biology,” he says. “That is what we are looking for in a probe.”

One hundred fifty validated probes have been created since the $70 million, 4 year production phase of the effort began in 2008, but only about 120 are publicly available due to the 1 year embargo. Full details on the available probes can be found at the MLP website (http://mli.nih.gov/mli/).

Screening, Et Al.

The data coming from the MLP includes information on the chemical structures as well as the assays and analytical tools regarding bioactivity.

“This lends real value to the program because each center in the MLP has a particular area of expertise regarding types of assays used or areas of research,” says Loomis.

But the MLP includes a bit more than small molecule screening. It also funds technology development encompassing new instrumentation, chemical diversity efforts including natural products methods, and pilot scale libraries to generate novel new compounds to put into the screening library. For example, researchers at the University of New Mexico, an MLP center, are adapting flow cytometry to high throughput screening.

Probe = Research Tool

MLP defines a probe as a compound that can be useful as a research tool. “It does not have to work in animals but ideally it will work in cells,” explains Loomis. “It could be a biochemical assay looking for a means to block a compound’s phosphorylation ability, or phenotypic assays.” The latter are of very high value to the MLP because these screens might point the way in finding a better target for a pathway.

The MLP emphasizes rare and neglected diseases, but they cover a large range of therapeutic areas including cancer, inflammation, infectious disease, and metabolic diseases. However, MLP funding is limited to the probe discovery process only. “If, with a little more study, some of these probes are found to be useful in animals and eventually becomes a lead for chemistry to develop a drug, that is a win/win for us, but our funding won’t go that far,” adds Loomis. If a probe discoverer believes it may represent a great opportunity for drug development, alternative funding is necessary.

“In my view, the most interesting and valuable part of the MLP program is the number of assays we have spanning multiple therapeutic areas or potential targets,” says Michelotti. In MLP, the assays are designed in a way to capture multiple levels of biological activity. “They also include information on potential roles of agonists, antagonists, partial agonists, etc., as the information we receive is denser, more rich, because it is not limited to one particular target.” And even within one target, Michelotti points out that the biological information is more comprehensive.

In the short time since full probe production began in September 2008, the MLP has become a go-to public resource in the burgeoning field of chemical probe production. With at least two more years of guaranteed funding, the number of new targets identified—and the probes to accompany them—will only rise in the hopes of quickening highly targeted drug discovery.

source: cell.com

Posted under Compound Screening, Drug Development, HT Screening, Press Releases  |  No Comments

Speeding up drug screening

Last Updated on Saturday, 24 July 2010 04:24 Written by Editor Monday, 12 July 2010 10:28

Box 1: Speeding up drug screening

Whole-cell assays allow new drugs to be screened for efficacy without knowing the molecular targets. High-throughput screens (HTSs) are vital in the quest for new compounds, but until recently have been lacking for Chagas disease.

At the Swiss Tropical and Public Health Institute, Reto Brun provides a ‘gold standard’ screening centre for protozoan parasites for the World Health Organization (WHO)–Special Programme for Research and Training in Tropical Diseases (TDR) and the Drugs for Neglected Diseases Initiative (DNDi), as well as the Gates-funded Consortium for Parasitic Drug Development (CPDD). His in vitro system involves the cultivation of Trypanosoma cruzi-infected rat myoblasts in 96-well microtitre plates, using genetically modified parasites that express a bacterial enzyme that can be quantified by photometry. This allows the screening of up to 1,000 compounds a week.

At the Sandler Center, husband-and-wife team Juan Engel and Patricia Doyle have created a medium-to-high-throughput system using a robotic liquid handler dispensing into 96-well microtitre plates. This uses an automated microscope to detect DNA-stained parasite kinetoplasts in primary cell cultures from skin, muscle, liver and macrophages, and quantifies the number of T. cruzi per host cell. Screening capacity has risen from 100 compounds a month to 1,000 compounds a week in whole-cell assays, or tens of thousands a week in enzyme biochemical assays.

Fred Buckner at the University of Washington Seattle in the United States has developed an HTS based on 384-well plates and recombinant T. cruzi expressing fluorescent β-galactosidase: “We’ve gone from an era where you could test a handful of compounds in a week to [one where it is possible to test] 250,000 in a few weeks. It’s helping everybody who’s interested in screening drugs — a much needed tool.” He has shared the system with laboratories in Brazil, Argentina, Panama, the United States and Europe.

LUCIO FREITAS-JUNIOR

Images of an osteoblast human cell line infected with Trypanosoma cruzi before (left) and after (right) software detection of cell boundaries.

One of the fastest HTS systems belongs to Lucio Freitas-Junior at the Institute Pasteur in Korea: a 384-well cell-culture system that combines an automated confocal microscope with an image analyser (pictured) to screen up to 30,000 compounds a week. Through DNA staining of wild-type rather than genetically modified T. cruzi, the system’s software can count the number of parasites per cell and the number of cells per well, measure the size and shape of each cell to give a read-out of viability and morphological change owing to parasite infection, and determine the effects of the would-be inhibitors. A second step selects compounds that interfere with replication of parasite kinetoplast DNA (which provides a specific set of targets that are relatively similar among T. cruzi, Trypanosoma brucei and Leishmania). Freitas-Junior and colleagues are now screening a Pfizer library of 150,000 compounds for leads against Leishmania and T. cruzi with a commission from the DNDi.

The HTS technology “has not been applied broadly in support of drug discovery for neglected diseases, so it presents a great opportunity to evaluate a large number of compounds to generate starting materials for further analysis”, says Solomon Nwaka of the WHO–TDR. Nonetheless, Nwaka is under no illusions about the difficulty of moving to the next state. “Just because you have a million compounds available to screen, doesn’t mean you will get a new drug. HTS just gets you to the next step”.

source: nature.com

Posted under Drug Development, HT Screening, Press Releases  |  No Comments

Increased R&D Efforts Are Overcoming Obstacles and Showing Potential

Last Updated on Saturday, 24 July 2010 10:26 Written by Editor Monday, 12 July 2010 09:46

Ion channels make good drug targets—they reside on the cell surface and are fast switching mechanisms. They act like cell transistors, controlling many cell processes. There are close to 500 types of ion channels, yet many remain undiscovered. This was mainly attributed to technology restraints, however, with the recent introduction of HT patch clamping, as well as new assays that facilitate faster, more robust screening, there are more ion channel receptors being detected.

Researchers at the recent Society for Biomolecular Screening conference and CHI’s upcoming “Pharmacology Driven Assays for GPCRs and Ion Channels” shared information on a cornucopia of topics, including the latest enabling technologies, new screening paradigms, and novel approaches to generate GPCRs.

The IonFlux system from Fluxion Biosciences was recently beta tested by scientists at Novartis Institutes for Biomedical Research (NIBR). “Compounds, buffers, and waste are contained on a single 96-well plate, eliminating robotic handling. Air pressure drives experiments in microfluidic channels in a layer below the wells. This is a novel approach in automated electrophysiology,” explained Andrew Golden, Ph.D., post-doc fellow.

Robustness is enhanced via recordings taken from 20-cell ensembles (IonFlux HT), and pharmacology improved by recording a full range of concentrations from the same group of cells, according to the company. There are two available systems—the IonFlux 16, which uses 96-well plates, and the IonFlux HT, which uses 384-well plates.

Analysis of the prototype (alpha and beta testing) was initially focused on whether IonFlux could reproduce results demonstrated on other platforms. “The microfluidic approach could be helpful for ligand-gated ion channels—especially for subsets of those for fast desensitizing ligand-gated ion channels where you only add a short pulse of the ligand or neurotransmitter,” explained Mats Holmqvist, Ph.D., research investigator in the center for proteomic chemistry at NIBR.

In addition, Dr. Holmqvist said the hope for the new platform is that it should provide selectivity not only by target but also by function. “You can utilize ‘use dependency’—the accumulation of inhibition with repetitive depolarizations. If an ion channel is active, the drug may be much more potent.” With this new technology, one should be able to refine and understand how a compound affects an ion channel. However, it’s still too early to show whether this will be the case.

Since HT platforms for ion channels are fairly new, standardization across different instruments hasn’t been addressed. “There are different quality control parameters, including the way of recording a single cell per well or ensemble recording in parallel. Some machines use Oracle database versus file formats. We’ve been trying to address that in safety profiling. A quick answer is that we make a summary PDF file of every compound in each experiment that can be accessed any time,” noted Dr. Holmqvist.

Parallel Screening

The traditional screening paradigm involves one target for primary HTS. However, this process “wastes a considerable amount of time to get results, and also wastes efforts on compound management in order to get those compounds ready for testing,” said Peter Hodder, Ph.D., senior director of lead identification for the translation research institute at the Scripps Institute, Florida.

His group uses a parallel screening process that screens compounds against the target and antitarget simultaneously. “Antitarget is an all-encompassing name for any assay you would run that’s different from the target—usually to remove compounds from further consideration,” Dr. Hodder explained. “We found most of those compounds are junk compounds anyway.” The antitarget becomes important for the hit compounds, because it provides information on whether it is something specific to the target or whether it is something nonspecific to the assay format.

Time saved via parallel screening can be four to five weeks per target. In addition, and what is more important and what is harder to gauge, he noted, is saved efforts following false trails, which result in smaller, cleaner datasets. Relevant structure  activity relationships emerge early in a campaign. For example, Dr. Hodder performed an SF1 (transcription factor) assay and ran the antitarget ROR against it and found potent compounds. “If we had relied on primary screening alone, those compounds would not have been selected.”

The parallel-screening format is not specific to any target class. “What’s more important is how to apply it to different target classes or different assay formats.” His group was successful in screening ion channels, including TRPML3 with TRPN1 as the antitarget (TRP is transient-receptor potential). HTS probes confirmed that the target is not located on plasma membranes in native cells.

Dr. Hodder added that this approach can be used to help focus on the most important compounds for drug or probe discovery, but it’s key is in choosing the right antitarget. “If it’s too close in relationship to the target, you’re going to start throwing out compounds you don’t want to during the campaign.”

His group is now performing more sophisticated screening using two or three antitargets and trying to find the overlap of hits that are specific in all three versus two or one of those targets and antitargets. “This challenges us to think about how we present and analyze our data.”

Novel Assays

Some of the challenges of working with ion channels include controlling activity, whether with a small molecule ligand or voltage. Many ion channels inactivate within milliseconds, making HTS difficult.

David Weaver, Ph.D., director at Vanderbilt Institute of Chemical Biology HTS, has been focusing his research efforts on ion channels—especially 7TM (7-Transmembrane) receptors.

“We are interested in looking at some of the effector systems that are more physiologically relevant and one of these is the GIRK (G-protein regulated inwardly rectifying potassium (K+) channel).” His group developed this assay to measure the activity of GI-coupled 7TM receptors. “The idea was whether we could see any differences in the pharmacology and the fact that we may be using a more physiologically relevant end effector rather than using mutant G proteins to couple the change in intracellular calcium.”

The success of the GIRK assay encouraged Dr. Weaver to examine ion channels as end effectors that could be used to generate new assays with physiological relevance. Preliminary data demonstrates the ability to detect changes in M-current (muscarinic-modulated potassium current, usually studied in the brain and peripheral nervous system) activity.

He developed an HTS-compatible assay that can measure and quantify the modulation of M-current downstream from the 7TM receptor using thallium-flux. This optical assay platform can use a commercially available kinetic imaging plate reader.

According to Dr. Weaver, the only nonstandard part of the assay is that he extracts a slope from the initial measurement, instead of fitting a peak amplitude. His hope is to use this assay to further understand the pharmacology of 7TM receptors. “It’s my intent that we can demonstrate that these are good, robust assays for use in HT screens to discover novel modulators of 7TM receptors or the ion channels we’re using as effectors.”

Novel Targets

“Ion channels are terrific molecular targets, and many drugs have been targeted to them,” stated David Clapham, M.D., Ph.D., Aldo R. Castenada professor of cardiovascular research at Children’s Hospital Boston. Yet, one of the biggest challenges is the gold standard assay—the patch clamp.

This is a time-consuming technique—single cell membranes must be broken open and the current must be recorded while controlling voltage in the cell. Although HT assays exist, not all ion channels are suited to them. “The most promising are the very fast, voltage-dependent channels with large, rapid changes and ones less amenable are ones that are similar to each other in their properties, like TRP channels—these are more difficult.”

Dr. Clapham also presented information on what he thought were good, fairly recent, ion-channel targets and included some recent data on some of his work with these targets.

Many TRP channels are involved in sensory functions, like smell, taste, and hearing. TRPV3 is an ion channel that is well expressed in skin. Dr. Clapham demonstrated that both skin barrier formation and some aspects of hair formation are altered by this ion-channel’s activation or block.

It is activated by subtle temperature changes—temperatures about 32ºC—indicating TRPV3 is sensing heat at the skin surface and relating that to the nerves. This indicates it may help regulate body temperature. Growth factors such as EPGR potentiates TRPV3 to bring calcium into karatinocytes, and, in turn, TRPV3 potentiates EPGR, so there’s a positive feedback loop.

“This is important for the proper formation of skin barriers, so that there is normally a cycle of karatinocytes maturing from deeper in the skin to the surface of the skin.” Dr. Clapham added that TRP channels are difficult to work with because they are fairly slow and their properties are often difficult to distinguish. In addition, they are often small in size, and there is a lack of known ways to activate them.

Additional ion channels that Dr. Clapham thought were worth pursuing were the NAV1.7 to NAV1.9 pain targets, which are voltage-gated sodium channels. A new chloride channel, TMAM16-A, and the ORAI channel, which is important in the immune system, were also on the list. An interesting new target for contraception, called CATSPER, is an ion channel only present in mature sperm and required for male fertility. “This may be a good method of contraception without hormones,” said Dr. Clapham.

“Our job is to find new targets and new molecules, and then other people can work with those molecules to target diseases.”

New Approach

There are many challenges for the generation of new GPCRs, said Michel Bouvier, Ph.D., professor and chairman in the department of biochemistry at the University of Montreal. These include selectivity and ligand-biased signaling, where one receptor can couple to different signaling pathways in a cell.

“The problem with this is that you are trying to monitor the efficacy of a compound toward one signaling pathway, but since there are multiple ones, we don’t necessarily know which one to follow that will correlate with a disease or particular activity.” His approach is to develop one assay that could encapsulate in one reading all the signaling pathways and by dissecting the signatures, provide information about the pathways being engaged by a receptor.

Utilizing Rocheâ™s label-free xCELLigence platform, his group is able to measure cell impedence. Each well of the plate has electrodes. As the cells grow, the impedance increases, and when the cells are treated with compounds that bind to receptors, many different pathways are triggered.

The readout reflects changes in impedance from the compound over time—providing a global assessment of the various pathways. Different compounds generate different curve shapes. “We can use this technology to differentiate classes of compounds that have different relative selectivity toward different pathways. It’s generating a simpler way to classify compounds in different efficacy profiles toward different signaling pathways.

Dr. Bouvier added that they can now, using selective inhibitors of different pathways  such as the generation of cyclic AMP, show how the inhibition influences the shape of the impedance curve. “Not only can we start classifying the ligands in different categories or compounds, but we can start making predictions on which pathways these compounds will be actively inhibiting. His group is planning to develop algorithms to apply to the curve and thus, provide a response as to which pathway is being affected. “We first need to confirm which portion of the curve informs us about each pathway.

This approach can be used for almost any receptors, reported Dr. Bouvier. It provides a big time savings—one assay instead of four or five. However, he added, “we don’t know yet if all signaling pathways will respond to changes in impedance—from our data so far, we haven’t encountered such a pathway.”

source: genengnews.com

Posted under Compound Screening, Drug Development, HT Screening, Press Releases  |  No Comments

Optimer Pharmaceuticals Receives Milestone Payment From Cempra for Next-Generation Macrolide Antibiotic

Last Updated on Saturday, 24 July 2010 04:26 Written by admin Thursday, 8 July 2010 11:02

SAN DIEGO, July 8 /PRNewswire-FirstCall/ – Optimer Pharmaceuticals, Inc. today announced it has received a $500,000 milestone payment from Cempra Pharmaceuticals, Inc. pursuant to the terms of a licensing agreement between the companies.  The milestone payment was made as a result of Cempra’s continuing development of a next-generation macrolide (CEM-101) for the treatment of respiratory infections. Cempra licensed CEM-101 from Optimer and has successfully completed a Phase 1 study.

“The successful completion of the CEM-101 Phase 1 study further validates our OPopSâ„¢ drug discovery platform. We are pleased to see this compound progress into the next phase of development by Cempra,” said Pedro Lichtinger, Optimer’s President and CEO.

CEM-101 is a next-generation oral macrolide entering Phase 2 clinical development for the treatment of community-acquired bacterial pneumonia (CABP). Cempra has exclusive worldwide rights, except in Association of Southeast Asian Nations, or ASEAN, countries, from Optimer to discover, develop and commercialize macrolides from a library of more than 500 compounds, including CEM-101, originated from Optimer’s OPopS drug discovery platform.

In vitro and in vivo studies of CEM-101 have shown potent activity against S. pneumoniae as well as an extended spectrum of activity against community-associated methicillin-resistant Staphylococcus aureaus (CA-MRSA), M. avium and in animal models of malaria. These studies have also indicated that CEM-101 is active against atypical bacteria, such as Legionella, Mycoplasma and Ureaplasma and against gonococci and other organisms that cause genitourinary tract infections.

About OPopSâ„¢

Optimer’s OPopS drug discovery platform allows the development of potential drug candidates through carbohydrate mediated medicinal chemistry and enables the rapid synthesis of a wide variety of proprietary molecules. It includes GlycoOptimization, which enables the modification of a carbohydrate group on an existing drug to improve its properties, and De Novo Glycosylation, which introduces new carbohydrate groups on existing drugs to create new patentable compounds with improvement of pharmacokinetics.

About Optimer Pharmaceuticals

Optimer Pharmaceuticals, Inc. is a biopharmaceutical company focused on discovering, developing and commercializing innovative anti-infectives to treat serious infections and address unmet medical needs. Optimer has two late-stage anti-infective product candidates under development. Fidaxomicin is a narrow spectrum antibiotic being developed for the treatment of Clostridium difficile infection (CDI).  In two Phase 3 trials completed by Optimer to study the safety and efficacy of fidaxomicin for the treatment of CDI, fidaxomicin was statistically superior to vancomycin in global cure rate (defined as cure with no recurrence within four weeks of completing therapy) as well as statistically superior in reducing recurrences of CDI by up to 50% when compared with vancomycin, the only FDA approved product for CDI. Pruvel™ is a prodrug in the fluoroquinolone class of antibiotics being developed as a treatment for infectious diarrhea.  Optimer has also successfully completed two Phase 3 trials with Pruvel.  Additional information can be found at http://www.optimerpharma.com.

Ranbaxy to transfer drug discovery unit to Daiichi Sankyo

Last Updated on Thursday, 8 July 2010 10:54 Written by admin Thursday, 8 July 2010 10:54

Jul 06, 2010 (Datamonitor via COMTEX) –

Daiichi Sankyo and Ranbaxy Laboratories, a research based pharmaceutical company, have announced that Ranbaxy’s new drug discovery research, or NDDR, has been transferred to Daiichi Sankyo India Pharma as part of the strategy to strengthen the global R&D structure of the Daiichi Sankyo Group.

The transaction has been reportedly approved by the Department of Scientific and Industrial Research, Ministry of Science and Technology, Government of India.

The new organization, Daiichi Sankyo Life Science Research Center (RCI) in India based in Gurgaon will play a key role in the group’s global drug discovery research – to create new drugs, especially in the area of low molecular weight infectious and inflammatory disease treatments. RCI will also reportedly continue to support the programs of dengue and tuberculosis that NDDR was working on in alliance with the department of biotechnology, Ministry of Science and Technology, Government of India.

Joji Nakayama, president and CEO of Daiichi Sankyo, said: “With the transfer of the NDDR into the Daiichi Sankyo Group’s pharmaceutical R&D organization, we will further strengthen our integrated global research capabilities through the addition of talented researchers who offer a new perspective and have a wealth
of imagination and experience. We look forward to achieving outstanding and innovative results based on the implementation of global research management throughout our highly diversified and global R&D structure.”


Ion Channels Open Doors to New Drugs Increased R&D Efforts Are Overcoming Obstacles and Showing Potential

Last Updated on Thursday, 8 July 2010 03:20 Written by Editor Thursday, 8 July 2010 03:20

  • Nina Flanagan
Ion channels make good drug targets—they reside on the cell surface and are fast switching mechanisms. They act like cell transistors, controlling many cell processes. There are close to 500 types of ion channels, yet many remain undiscovered. This was mainly attributed to technology restraints, however, with the recent introduction of HT patch clamping, as well as new assays that facilitate faster, more robust screening, there are more ion channel receptors being detected.

Researchers at the recent Society for Biomolecular Screening conference and CHI’s upcoming “Pharmacology Driven Assays for GPCRs and Ion Channels” shared information on a cornucopia of topics, including the latest enabling technologies, new screening paradigms, and novel approaches to generate GPCRs.

The IonFlux system from Fluxion Biosciences was recently beta tested by scientists at Novartis Institutes for Biomedical Research (NIBR). “Compounds, buffers, and waste are contained on a single 96-well plate, eliminating robotic handling. Air pressure drives experiments in microfluidic channels in a layer below the wells. This is a novel approach in automated electrophysiology,” explained Andrew Golden, Ph.D., post-doc fellow.

Robustness is enhanced via recordings taken from 20-cell ensembles (IonFlux HT), and pharmacology improved by recording a full range of concentrations from the same group of cells, according to the company. There are two available systems—the IonFlux 16, which uses 96-well plates, and the IonFlux HT, which uses 384-well plates.

Analysis of the prototype (alpha and beta testing) was initially focused on whether IonFlux could reproduce results demonstrated on other platforms. “The microfluidic approach could be helpful for ligand-gated ion channels—especially for subsets of those for fast desensitizing ligand-gated ion channels where you only add a short pulse of the ligand or neurotransmitter,” explained Mats Holmqvist, Ph.D., research investigator in the center for proteomic chemistry at NIBR.

In addition, Dr. Holmqvist said the hope for the new platform is that it should provide selectivity not only by target but also by function. “You can utilize ‘use dependency’—the accumulation of inhibition with repetitive depolarizations. If an ion channel is active, the drug may be much more potent.” With this new technology, one should be able to refine and understand how a compound affects an ion channel. However, it’s still too early to show whether this will be the case.

Since HT platforms for ion channels are fairly new, standardization across different instruments hasn’t been addressed. “There are different quality control parameters, including the way of recording a single cell per well or ensemble recording in parallel. Some machines use Oracle database versus file formats. We’ve been trying to address that in safety profiling. A quick answer is that we make a summary PDF file of every compound in each experiment that can be accessed any time,” noted Dr. Holmqvist.

Parallel Screening

The traditional screening paradigm involves one target for primary HTS. However, this process “wastes a considerable amount of time to get results, and also wastes efforts on compound management in order to get those compounds ready for testing,” said Peter Hodder, Ph.D., senior director of lead identification for the translation research institute at the Scripps Institute, Florida.

His group uses a parallel screening process that screens compounds against the target and antitarget simultaneously. “Antitarget is an all-encompassing name for any assay you would run that’s different from the target—usually to remove compounds from further consideration,” Dr. Hodder explained. “We found most of those compounds are junk compounds anyway.” The antitarget becomes important for the hit compounds, because it provides information on whether it is something specific to the target or whether it is something nonspecific to the assay format.

Time saved via parallel screening can be four to five weeks per target. In addition, and what is more important and what is harder to gauge, he noted, is saved efforts following false trails, which result in smaller, cleaner datasets. Relevant structure  activity relationships emerge early in a campaign. For example, Dr. Hodder performed an SF1 (transcription factor) assay and ran the antitarget ROR against it and found potent compounds. “If we had relied on primary screening alone, those compounds would not have been selected.”

The parallel-screening format is not specific to any target class. “What’s more important is how to apply it to different target classes or different assay formats.” His group was successful in screening ion channels, including TRPML3 with TRPN1 as the antitarget (TRP is transient-receptor potential). HTS probes confirmed that the target is not located on plasma membranes in native cells.

Dr. Hodder added that this approach can be used to help focus on the most important compounds for drug or probe discovery, but it’s key is in choosing the right antitarget. “If it’s too close in relationship to the target, you’re going to start throwing out compounds you don’t want to during the campaign.”

His group is now performing more sophisticated screening using two or three antitargets and trying to find the overlap of hits that are specific in all three versus two or one of those targets and antitargets. “This challenges us to think about how we present and analyze our data.”

Novel Assays

Some of the challenges of working with ion channels include controlling activity, whether with a small molecule ligand or voltage. Many ion channels inactivate within milliseconds, making HTS difficult.

David Weaver, Ph.D., director at Vanderbilt Institute of Chemical Biology HTS, has been focusing his research efforts on ion channels—especially 7TM (7-Transmembrane) receptors.

“We are interested in looking at some of the effector systems that are more physiologically relevant and one of these is the GIRK (G-protein regulated inwardly rectifying potassium (K+) channel).” His group developed this assay to measure the activity of GI-coupled 7TM receptors. “The idea was whether we could see any differences in the pharmacology and the fact that we may be using a more physiologically relevant end effector rather than using mutant G proteins to couple the change in intracellular calcium.”

The success of the GIRK assay encouraged Dr. Weaver to examine ion channels as end effectors that could be used to generate new assays with physiological relevance. Preliminary data demonstrates the ability to detect changes in M-current (muscarinic-modulated potassium current, usually studied in the brain and peripheral nervous system) activity.

He developed an HTS-compatible assay that can measure and quantify the modulation of M-current downstream from the 7TM receptor using thallium-flux. This optical assay platform can use a commercially available kinetic imaging plate reader.

According to Dr. Weaver, the only nonstandard part of the assay is that he extracts a slope from the initial measurement, instead of fitting a peak amplitude. His hope is to use this assay to further understand the pharmacology of 7TM receptors. “It’s my intent that we can demonstrate that these are good, robust assays for use in HT screens to discover novel modulators of 7TM receptors or the ion channels we’re using as effectors.”

Novel Targets

“Ion channels are terrific molecular targets, and many drugs have been targeted to them,” stated David Clapham, M.D., Ph.D., Aldo R. Castenada professor of cardiovascular research at Children’s Hospital Boston. Yet, one of the biggest challenges is the gold standard assay—the patch clamp.

This is a time-consuming technique—single cell membranes must be broken open and the current must be recorded while controlling voltage in the cell. Although HT assays exist, not all ion channels are suited to them. “The most promising are the very fast, voltage-dependent channels with large, rapid changes and ones less amenable are ones that are similar to each other in their properties, like TRP channels—these are more difficult.”

Dr. Clapham also presented information on what he thought were good, fairly recent, ion-channel targets and included some recent data on some of his work with these targets.

Many TRP channels are involved in sensory functions, like smell, taste, and hearing. TRPV3 is an ion channel that is well expressed in skin. Dr. Clapham demonstrated that both skin barrier formation and some aspects of hair formation are altered by this ion-channel’s activation or block.

It is activated by subtle temperature changes—temperatures about 32ºC—indicating TRPV3 is sensing heat at the skin surface and relating that to the nerves. This indicates it may help regulate body temperature. Growth factors such as EPGR potentiates TRPV3 to bring calcium into karatinocytes, and, in turn, TRPV3 potentiates EPGR, so there’s a positive feedback loop.

“This is important for the proper formation of skin barriers, so that there is normally a cycle of karatinocytes maturing from deeper in the skin to the surface of the skin.” Dr. Clapham added that TRP channels are difficult to work with because they are fairly slow and their properties are often difficult to distinguish. In addition, they are often small in size, and there is a lack of known ways to activate them.

Additional ion channels that Dr. Clapham thought were worth pursuing were the NAV1.7 to NAV1.9 pain targets, which are voltage-gated sodium channels. A new chloride channel, TMAM16-A, and the ORAI channel, which is important in the immune system, were also on the list. An interesting new target for contraception, called CATSPER, is an ion channel only present in mature sperm and required for male fertility. “This may be a good method of contraception without hormones,” said Dr. Clapham.

“Our job is to find new targets and new molecules, and then other people can work with those molecules to target diseases.”

New Approach

There are many challenges for the generation of new GPCRs, said Michel Bouvier, Ph.D., professor and chairman in the department of biochemistry at the University of Montreal. These include selectivity and ligand-biased signaling, where one receptor can couple to different signaling pathways in a cell.

“The problem with this is that you are trying to monitor the efficacy of a compound toward one signaling pathway, but since there are multiple ones, we don’t necessarily know which one to follow that will correlate with a disease or particular activity.” His approach is to develop one assay that could encapsulate in one reading all the signaling pathways and by dissecting the signatures, provide information about the pathways being engaged by a receptor.

Utilizing Roche’s label-free xCELLigence platform, his group is able to measure cell impedence. Each well of the plate has electrodes. As the cells grow, the impedance increases, and when the cells are treated with compounds that bind to receptors, many different pathways are triggered.

The readout reflects changes in impedance from the compound over time—providing a global assessment of the various pathways. Different compounds generate different curve shapes. “We can use this technology to differentiate classes of compounds that have different relative selectivity toward different pathways. It’s generating a simpler way to classify compounds in different efficacy profiles toward different signaling pathways.”

Dr. Bouvier added that they can now, using selective inhibitors of different pathways  such as the generation of cyclic AMP, show how the inhibition influences the shape of the impedance curve. “Not only can we start classifying the ligands in different categories or compounds, but we can start making predictions on which pathways these compounds will be actively inhibiting. His group is planning to develop algorithms to apply to the curve and thus, provide a response as to which pathway is being affected. “We first need to confirm which portion of the curve informs us about each pathway.”

This approach can be used for almost any receptors, reported Dr. Bouvier. It provides a big time savings—one assay instead of four or five. However, he added, “we don’t know yet if all signaling pathways will respond to changes in impedance—from our data so far, we haven’t encountered such a pathway.”

source: genengnews.com

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Leading the way

Last Updated on Friday, 14 May 2010 11:06 Written by Editor Friday, 14 May 2010 11:06

Successful drug research depends on high-quality hits in early screening. Trevor Perrior, research director at Domainex, explains why researchers are adopting a new method that turns high-throughput screening on its head

To some people, high-throughput screening (HTS) is synonymous with finding hits. But is it the best and only system? More and more drug researchers say they are looking for a faster and more cost-effective replacement. LeadBuilder was developed as an alternative to HTS that saves time and money because only compounds likely to become a drug are screened. HTS works the opposite way round – it ploughs through an enormous, random library of compounds and the hits are tested afterwards to find the most ‘drug-like’.

HTS is like searching for a needle in a vast haystack using a bulldozer. It is expensive because – paradoxically – the chance of finding the needle increases if you have more hay in which to look. Hundreds of thousands, or even millions, of compounds must be collected before HTS can begin. You also need to buy the bulldozer. Equipment like assay platforms and automated machinery must be purchased. HTS has high ongoing costs too, such as reagents, supplying proteins or cells, and replenishing the compound collection over time.

Once the equipment is running, screening seems very fast at first glance. Some estimates claim 10,000–100,000 compounds a day can pass through an HTS system. But preparing for HTS is an often forgotten time-sink. It takes time to establish a robust assay suitable for HTS and to obtain enough high-quality protein or cells to screen the whole compound collection.

Analysing HTS results is also time-consuming. Bulldozing your way randomly through any old compounds means hits often are not very ‘drug-like’. Hundreds of hits must be exhaustively tested for safety, bioavailability, novelty and affinity for the target.

A decade ago, it was less important that HTS was expensive and hard to set up. Big pharmaceutical companies with large budgets and laboratories did most drug discovery. Now, spin-off companies, small biotechs, research institutions and academic labs are increasingly getting in on the act. Many cannot afford to run an HTS operation in-house or pay perhaps £100,000–£250,000 to outsource a screen.

LeadBuilder turns HTS on its head. Instead of screening everything, the system physically screens only compounds that look like drugs or hits. Returning to our haystack idea, the system only picks short “needle-like” straws, making it easier to find the ones that really shine

Based on state-of-the-art virtual modelling and screening software, LeadBuilder has four main modules: LibraryBuilder, CompoundProfiler, ScreenBuilder and StructureBuilder


The system starts with CATS (Compounds Available To Screen). These are a set of commercially available compounds sourced from reliable suppliers stored in the LibraryBuilder module.

ranked by drug potential

CompoundProfiler finds NICE (Interesting Chemical Entities) CATS by calculating each CATS’ molecular properties and predicting its physiochemical, pharmacokinetic and toxicity profile
CATS are then ranked by how ‘drug-like’ they are. NICE CATS meet every criterion for the ‘perfect’ screening hit – they have excellent molecular properties, good ADME, low toxicity and interact well with a target protein.

Choosing NICE CATS involves creative thinking about what makes a ‘drug-like’ compound. For example, after reviewing 37 hit-to-lead programmes, we found that high ligand efficiency (binding energy per atom) predicted hits that were easy to optimise into drug candidates. Higher ligand efficiencies resulted from certain structural features like charged groups (e.g. N+). So Domainex developed an algorithm that predicts a ligand efficiency from a compound’s structural features. We use this to eliminate poorly performing CATS.

The next stage in building leads is ScreenBuilder – a virtual screening engine that works on NICE CATS. Using information about the target protein, any known ligands or both of these, this module can screen by a com­bination of docking, pharmacophore searches and privileged fragment recognition. If the target protein is unknown, the system can identify a surrogate with a similar active siteThree real-life examples can illustrate how ScreenBuilder works: first, screening with pharmacophores derived from a known ligand, followed by docking into the x-ray structure of a protein; second, searching with ligand-based pharmacophores; and third, using only information about the target protein structure.

Example 1: Finding small molecules to inhibit protein-protein or peptide-peptide interactions is notoriously difficult. But LeadBuilder managed it. ScreenBuilder found 47 compounds that blocked a growth factor – natural peptide – from binding to its protein receptor. Aberrant growth factor signalling often drives tumour growth.

Domainex was given an x-ray structure of the ligand-binding pocket of the growth factor receptor with an oligopeptide fragment of the growth factor ligand bound to it. LeadBuilder analysed the ligand-binding pocket to define search criteria. Several structural features of the oligopeptide – H-bond donors and acceptors and a lipophilic group – seemed essential for binding to the receptor.

Next, the NICE database was virtually screened for compounds that contained these features and could be ‘docked’ into the protein’s active site. Domainex’s client lined up a subset of these compounds for further screening.

The project is currently in its hit-to-lead phase. Altogether, LeadBuilder identified 950 compounds for screening, delivering a 5% hit rate over several structural types. This made it 10 times more productive than another vendor’s focused library of 1000 compounds, which found only five hits (0.5% hit rate).

Example 2: A patent was filed on several compounds identified during another LeadBuilder project because they had commercially interesting activity levels. Domainex had been just given one known ligand to work with. The client was interested in compounds that would stimulate bone growth to accelerate the healing of fractures. It had developed a cell-based assay to look for compounds that switched on a signalling pathway that would cause deposition of bone. The ligand given to Domainex as a starting point was the only stimulator it had found for the pathway – it was keen to find others as potential drugs and for mechanism-of-action studies.

Domainex screened the NICE database using three pharmacophoric features based on the known ligand. Around 100 compounds were selected for screening, with the emphasis being on cellular penetration. During screening, our client found a hit with five times the activity of the known ligand. We are now helping it with a follow-up medicinal chemistry programme to find even better compounds.

Example 3: Protein kinases are important drug targets for a number of diseases. Many of the known inhibitors work by competing with the kinase substrate ATP. The problem with this approach is that it is difficult to find compounds that stop ATP binding to one kinase, but have no effect on the binding of ATP to other kinases. This selectivity problem means that kinase inhibitors often have side-effects caused by them blocking non-target kinase enzymes.

Our client wanted to find a selective inhibitor of a kinase that is a well-known cancer target, and had a novel hypothesis – did this protein kinase have a natural regulatory site that they could exploit with small-molecule drugs? The answer was yes. The client has patented the IP and is using it to secure funds. Domainex is now helping it develop a programme to turn its hits into leads.

An x-ray structure of the kinase showed that, in the naturally occurring inactive form, part of the enzyme ‘loops’ around to block the substrate protein binding site. On activation, this loop must move away to reveal a groove on the enzyme where the protein substrate can bind. An inhibitor that sits in this groove would stop catalysis by the kinase.

LeadBuilder found a four-point pharmaco-phore based on the key features of the “autoinhibitory loop” and an analysis of its binding groove on the surface of the enzyme (see Fig. 5). Using ScreenBuilder, potential ligands were selected from the NICE database using this pharmacophore and were docking into the hypothesised binding pocket.

Domainex recommended that the client screen 450 compounds based on this research. When tested against the kinase, this gave a 6% hit rate – 27 hits in four structural classes. Four of these showed promise in a follow-up cell-based screen.

In conclusion, dissatisfaction with HTS is growing. To many, finding hits seems like looking for a needle in a haystack. LeadBuilder is a smarter alternative. It may not yet offer pinpoint accuracy, but it can deliver ten times more hits during drug development.

source: manufacturingchemist.com

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AFraxis CEO Outlines Biotech’s Success With Ultra-Lean Pre-Clinical R&D in Russia

Last Updated on Wednesday, 12 May 2010 02:49 Written by Editor Wednesday, 12 May 2010 02:49

AFraxis, a mostly stealthy San Diego biotech, is getting ready to come out with a big announcement in the next week or so, but CEO Jay Lichter previewed some key parts of the story yesterday during a presentation before the San Diego Venture Group. He says the biotech has completed pre-clinical testing of a promising compound for treating a form of autism related to Fragile X syndrome.

Lichter, who does double duty as a managing partner of San Diego-based Avalon Ventures, founded aFraxis in 2007—shortly after researchers identified a possible drug target for Fragile X, a family of related mental disorders caused by a defect (or multiple defects) in a single gene on the X chromosome.

Of course, finding a compound that fits a single molecular target (the way a key fits into a lock) is no simple matter. The process can require screening millions of compounds, and then researchers must determine if candidate compounds are reasonably safe for initial use in humans and show the relevant pharmacological activity that justifies commercial development.

“The goal is to make a single exploratory compound and test it in a mouse, and we’ve done that,” Lichter says. The aFraxis CEO didn’t provide a lot of new details about the science. The target, which was identified at MIT in Nobel laureate Susumu Tonegawa’s laboratory, is PAK, a specific group of enzymes that catalyze neural reactions. Lichter says the same mechanism appears to be in play with schizophrenia. As Denise reported earlier this month, Fragile X Syndrome, which is the most common known cause of autism, is believed to be caused by defects in the gene that produces this group of enzymes.

Lichter’s presentation was instead focused mostly on the ultra-lean company-building approach aFraxis has taken to get this far. After three years, he says the biotech has only a handful of employees, and Avalon has invested a total of roughly $6 million to basically get to a stage where the company could submitt an application to begin clinical trials. “We started from scratch from a paper in PNAS (Proceedings of the National Academy of Sciences,” Lichter says.

The pre-clinical research was done in record time—and at a savings of roughly $4 million—by joining forces with Torrey Pines Investment, Lichter says. Torrey Pines Investment, a San Diego life sciences investment firm, happens to own a full-service contract research organization near Moscow. AFraxis plans to begin tests in Russia in 2011 to evaluate the drug’s safety in humans, Lichter says. If all goes as planned, he says tests in Fragile X patients in Moscow will follow.

Nicolay Savchuk, a Russian-born mathematician and director of Torrey Pines Investment who also participated in the presentation, says his firm uses its ties with the Moscow-based Chemical Diversity Research Institute to focus “on the gap where [potential drug] compounds are and where they need to be.” Savchuk says his firm likes to invest in potential drug candidate “assets” and use its R&D capabilities to produce “data packages” that provide the validation necessary to eventually turn its assets into drugs.

Savchuk says the deal with Avalon and aFraxis was “unusual and out-of-the-box thinking” made possible because “Jay was very seductive” and offered Torrey Pines an opportunity to make a direct investment in aFraxis. In exchange for an equity stake in the San Diego biotech, Savchuk says his firm guaranteed to cover the costs of the pre-clinical research and development that was done by the Russian CRO.

“I would not say it’s a one-size-fits-all model,” Savchuk says. “But it is a way to do more.”

Lichter added that he personally reviewed the capabilities of the Russian CRO, and was deeply impressed by the institute’s “top-notch’ capabilities in medicinal chemistry, biology, and related fields of drug research and development. He says he also was assured by the fact that Savchuk lives and works “just down the street.” Lichter says the Russian CRO’s cost was competitive with Asian firms, but that Savchuk’s personal involvement was a crucial factor—and a principal reason why Lichter could not envision doing the same work with an unfamiliar CRO in India or China.

“There’s something to be said about good neighbors,” Savchuk agreed. “We saw these target-to-clinic capabilities [that we have] as a convenient way to de-risk [biotech] investments. It made sense to us and our partners to streamline costs as much as possible.”

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« Community Group Loses City Funding More Restaurants on Noe Valley’s 24th Street? » UCSF Lab Uses Brains & Street Smarts to Fight Deadly Parasite

Last Updated on Wednesday, 12 May 2010 02:46 Written by Editor Wednesday, 12 May 2010 02:46

A few years ago a chemist made an offer under the table to Jim McKerrow, a professor at UC San Francisco’s Mission Bay campus. McKerrow accepted and drove down to South San Francisco, backed his car up to a loading dock, filled the trunk, and drove away.

“Suddenly I think, oh wow. What if I get stopped by the highway patrol and they open the trunk and there’s all these vials with white powder,” he said, recalling the incident recently. “Now officer, these are protease inhibitors,” he joked.

Back in the mid-1990s, McKerrow adopted another protease inhibitor, K777, in a similarly altruistic maneuver with Jim Palmer, a chemist then working at the now defunct Khepri Pharmaceuticals.

Today, that compound has become a promising candidate in the fight against an infectious parasite that has been found in the Bay Area blood supply and affects millions of victims in Latin America. The culprit—Trypanosoma cruzi (trip-PAN-o-soma CREW-see) —causes the potentially-fatal Chagas disease.

If K777 is successful, which won’t be known until it goes through lengthy clinical trials, it will be the first drug out of UCSF developed independently from industry. In this case, that research was conducted by McKerrow’s lab and its collaborators at the Sandler Center for Basic Research into Parasitic Diseases, a consortium devoted to drug development for neglected diseases.

The latter are infections that are endemic but primarily affect poor people. With Chagas, it’s 8 to 12 million of them, nearly all having lived in rural Latin America at some point in their lives.

An obsolete Brazilian 10,000 cruzado note reflects the importance of the disease in that country, where it was first discovered.

“Instead of on American money – e pluribus unum – here is the life cycle of the parasite sucking blood from someone’s skin,” McKerrow said, pulling a bill out of his desk drawer and pointing to money, which shows a drawing of a benchuca and the skin of its victim, complete with bite mark and parasite-rich feces.

Spread By A Bloodsucking Vector

The T. cruzi parasite – a single-celled eukaryote – is spread by a bloodsucking subfamily of assassin bug called a benchuca, or kissing bug. It bites near a sleeping victim’s eye or mouth, hence its name.

Every time a benchuca has a blood meal, it also defecates. T. cruzi moves from bug to human host when the victim inadvertently scratches the its poop into the bite wound or a mucus membrane.

The Centers for Disease Control and Prevention believe that almost all infections happen outside of the United States, but the parasite, and the insect that spreads it, live in the Southwest and some parts of California. It can also infect animals.

If untreated, 20 to 30 percent of its victims will develop significant, sometimes fatal heart disease, according to the CDC.

No Financial Incentives to Study Chagas

Because the poor are most affected, Chagas isn’t an interesting investment for pharmaceutical development, but it remains important to researchers and countries like Brazil, Argentina, and Bolivia, which have pockets of very high incidence. It’s that importance that leads some to make calls to fellow chemists like McKerrow.

Labs have no financial incentive to look into alternatives to the available treatment for the parasite — nasty drug regimens developed around WWII that have serious side effects including vomiting, psychiatric effects, and nerve damage. But still, scientists remain interested and aware that the latter might be improved on.

So when lawyers for the closing South San Francisco life sciences company told their scientists to destroy the compounds they had been working on to avoid any legal problems, the chemist thought it worth the risk to call McKerrow.

Some of these otherwise doomed compounds, he or she suspected, might be useful to the Sandler Center in fighting parasitic diseases like Chagas and malaria. McKerrow declined to name the chemist.

“It would be a terrible shame to waste stuff in which millions of dollars had been poured into,” Jim Palmer said generally about drugs developed in industry that might get thrown away.

Years earlier, Palmer made a batch of K777 for McKerrow in his free time, hoping the compound would have potential to help treat parasitic infections.

Palmer now works in Australia and said that everything he did with McKerrow was above board, though there are indications that some higher ups in his company at the time – long since dissolved – were uninformed about the relationship initially. “I don’t know anything about that – I don’t remember,” Palmer said.

Palmer was happy about the compound´s progress. He said he named after he saw the very first Boeing 777 airplane waiting to enter service at Dulles International Airport. “It’s like my child,” he said.

K777 was one of about 20 compounds – initially investigated for applications like cancer and arthritis – that were handed over to McKerrow to match against a chemical produced by the Chagas disease parasite.

McKerrow said that the compound has since been legally secured, safe from anyone being able to take out a patent and charge huge sums for it if it.

Though getting drug company throwaways helps, having promising compounds is merely one of many steps in a long and expensive drug development process.

Sandler Center researcher at a chemical hood.

Researchers screened thousands of compounds along the way. Tests for the disease had to be created, as did an animal model, which were designed through the devoted efforts of scientist couple Patricia Doyle-Engle and Juan Engle, according to McKerrow.

The Sandler Center targeted Chagas in particular because Latin American countries have basic infrastructure, like clinics, to distribute medicines once they are developed.

McKerrow said there won’t be a vaccine, since vaccines function to boost immune function, and in later stages of the disease, the host’s own immune response to T. cruzi helps damage heart tissue. Furthermore, there are wild animals like armadillos that are reservoirs for the disease. It’s impossible to eradicate.

Instead, researchers at the Sandler Center are looking at possible drug treatment – protease inhibitors – that stop the action of a chemical the parasite requires throughout its life cycle.

So far, K777 has been shown to be effective in animal tests. The next step is a clinical trial in humans. McKerrow said that the next hurdle is raising roughly $350,000 to pay for manufacturing the drug for such a study according to FDA standards.

Parasites in the Blood Supply

Meanwhile, on the local level, other researchers are tracking Chagas through blood donations.

Studies conducted by San Francisco-based Blood Systems Research Institute found that one out of every 16,000 donors in the San Francisco area tested positive for the parasite. That’s about double the overall U.S. rate.

The CDC estimates roughly 300,000 immigrants have the parasite in the United States.

“Nobody is legally required to screen for T. cruzi in the U.S.,” said Brian Custer, an associate investigator at the institute. He estimated 75 to 80 percent of blood banks nationwide are screening for it, and probably all California blood banks screen for it.

He said he didn’t know anybody that was doing really good outreach, adding that the institute tried to form outreach partnerships with local organizations and clinics, but it was “very, very unsuccessful.”

The American Red Cross and the institute are the largest blood research entities in the country and the only blood banks studying the infection. Custer said the Blood Systems Research Institute is in an ongoing study of the parasite in Brazil, because little data exists on how Chagas disease progresses after initial infection.

“We really don’t know how it’s contributing to the overall burden of heart disease in the United States,” Custer said.

Rare cases of transmission have occurred in this country. However, infection is closely associated with substandard housing – the benchuca likes crevices that exist in thatched housing – and the vast majority of infections are linked to time spent in certain rural areas of Latin America.

Areas of Argentina have some of the highest prevalence of infection, yet “the likelihood of someone in Buenos Aires having T. cruzi is about the same as someone in San Francisco having the infection,” Custer cautioned.

It’s a disease, like many, with a long tail and may have felled one of the most famous scientists of all.

Charles Darwin wrote about being bitten by a benchuca and suffered from a mysterious illness his whole life. He died from heart failure, and some believe he may have had Chagas.

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Pharmatek Laboratories Receives DEA Registration for Handling Controlled Substances

Last Updated on Wednesday, 12 May 2010 02:35 Written by Editor Wednesday, 12 May 2010 02:35

Pharmatek Expands its Capabilities in Providing Comprehensive Drug Development and Manufacturing Services
SAN DIEGO, Feb. 17 /PRNewswire/ — Pharmatek Laboratories, Inc., a premier contract development and manufacturing organization supporting the pharmaceutical industry, announced that it has successfully met Drug Enforcement Agency (DEA) requirements to be registered for the development and manufacture of Schedule IV and V controlled substances.”Based on the needs of our clients, Pharmatek has put significant systems in place for the handling, inventory, development and manufacture of controlled substances,” said Kevin Rosenthal, Director of Manufacturing.   “Being registered by the DEA validates our facility design, security systems, and procedures for manufacturing, handling, storage and disposal meet the stringent requirements of the DEA.”

Controlled substances are designated as Schedule I-V according to their medical use, potential for abuse and safety or dependence liability.  In order to research, manufacture or distribute a controlled substance, a person or entity must be audited and registered by the DEA.

“Our goal is to continue to strive to meet the needs of our existing and prospective clients by adding to our capabilities in pharmaceutical chemistry development and manufacturing,” said Timothy Scott, President at Pharmatek.  “As a client-centric organization, our success is predicated on our ability to serve our clients.  We are happy to bring this additional capability to Pharmatek in order to serve that purpose.”

About Pharmatek Laboratories, Inc.

Pharmatek Laboratories Inc. is a premier pharmaceutical chemistry development company providing full-service pharmaceutical chemistry product development for the pharmaceutical industry.  Pharmatek focuses on bringing client compounds from discovery to the clinic with services that include compound selection, analytical development, preformulation testing, formulation development, GMP manufacturing, stability storage and testing, and cytotoxic and high-potency development.

Statements contained in this media release which are not historical facts may constitute forward-looking statements.  All forward-looking statements are subject to risks and uncertainties which could cause actual results to differ from those projected including sales forecasts and strategic expansion.  The trademarks Pharmatek, Pharmatek Laboratories, Inc., Hot Rod Chemistry, Pharmatek Formulation Screening, Pharmatek University and PTEK U are all property of Pharmatek Laboratories, Inc.  Additional information about Pharmatek Laboratories may be obtained at the Web site http://www.pharmatek.com or by calling 858-805-6383.

source: fiercebiotech.com

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Nausea drug may treat heart disease

Last Updated on Wednesday, 12 May 2010 01:53 Written by Editor Wednesday, 12 May 2010 01:53

American scientists have identified new effects of drugs approved by Food and Drug Administration (FDA), which can help shift cellular energy metabolism and may even come useful in the treatment of cardiovascular disease.

The findings of the study team, led by Massachusetts General Hospital (MGH) researchers, have appeared in Nature Biotechnology . One of the key findings of the study was meclisine, a well-known nausea drug, may help treat heart disease and stroke. Initial studies in animals using meclisine, a drug commonly used to treat nausea and vertigo, have given favourable results in treating cardiovascular diseases and stroke. Vamsi Mootha of the MGH Center for Human Genetic Research, who led the study, said, ‘Shifts in cells’ energy production pathways take place naturally during development and in response to demanding activities – like sprinting versus long-distance running. They are also known to be involved in several disease states.

“We wanted to identify compounds that can safely induce this shift – those that have previously been discovered are too toxic – and investigate their therapeutic potential in animal models.” Usually cells convert nutrients into energy by relying on two cellular processes. One involves the uptake of sugars that are broken down in the cytoplasm into a molecule called lactate by a process called glycolysis, which quickly yields a small amount of ATP, the enzyme that provides cellular energy. Alternatively, sugars and proteins can be processed in cellular structures called mitochondria to release greater amounts of ATP through a more efficient process called cellular respiration.

In cancer cells and other rapidly proliferating cells, energy is produced predominantly by glycolysis, suggesting that a shift away from that mechanism might suppress tumour growth. Previous animal studies suggested that a reduction in mitochondrial respiration could mimic a process called ischemic preconditioning, in which brief episodes of ischemia – a reduction in blood flow – actually protect tissue against being damaged if its blood supply is later cut off completely.

To look for compounds that shift cells from respiration to glycolysis, Mootha’s team devised a unique screening strategy. The scientists cultured skin cells in two different nutrient environments – glucose, which provides energy through both glycolysis and respiration, or galactose, which forces cells to rely on mitochondrial respiration alone. A drug that redirects energy metabolism from respiration to glycolysis would stop growth in the galactose- cultured cells while having little effect on cells grown in glucose. Their initial screen of almost 3,700 compounds, including nearly half of all FDA-approved drugs, found several drugs known to inhibit cellular respiration on one end of the scale and several anti-cancer drugs that halt the growth of rapidly proliferating cells at the other, which verified the approach.

Because most agents known to mimic ischemic preconditioning in animal models are too toxic to use in human patients, the researchers were quite eager to find drugs that cause subtle metabolic shifts. The screen identified eight approved drugs that produced a less pronounced but still significant shift away from cellular respiration. One of those agents was meclisine.

To study meclisine’s potential to prevent tissue damage in heart attack or stroke, Mootha’s team joined hands with University of Rochester researchers who had developed rat models of heart attack damage and an MGH Pathology group with a mouse model of stroke damage. Blinded experiments using both animal models showed that pretreatment with meclisine dramatically reduced ischemic damage to cardiac cells in the heart attack model and to brain cells in the stroke model. They also discovered that meclisine’s ischemia protective effects do not appear to involve its known mechanisms.

While the study results suggest that treatment with drugs like meclisine may someday be useful for reducing the damage associated with heart attack or stroke, Mootha believes much additional study is needed. He said, “Before we can think about human studies, we need to do rigorous animal testing to determine optimal, safe dosing regimens and learn more about how this drug works.”
source: indiatimes.com

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Experimental drug shows some benefit for Huntington’s disease

Last Updated on Wednesday, 12 May 2010 01:32 Written by Editor Wednesday, 12 May 2010 01:32

An experimental drug call latrepirdine has produced a small improvement in the mental abilities of some patients with Huntington’s disease, a finding that sets the stage for a larger clinical trial. Although the improvement was modest, the study marks the first time that a drug has been shown to improve brain function in the disorder.

Huntington’s is one of the more common inherited brain disorders. About 25,000 Americans have it and an additional 60,000 carry the defective gene that causes it and will develop the disorder as they age. It strikes between age 30 and 50 and is characterized by jerky, involuntary movements called chorea; loss of control of bodily functions; and dementia, a progressive deterioration of memory and thought processes. The only drug formally approved for treatment of Huntington’s is tetrabenazine, which improves chorea but does nothing for mental faculties.

Latrepirdine was originally developed in Russia nearly three decades ago as a treatment for hay fever, but it is no longer sold anywhere. Russian researchers screening compounds for potential effects on the brain found that it appears to stabilize mitochondria, the power source of brain and other cells. Because of that activity, Medivation Inc. of San Francisco and Pfizer Inc, which purchased the rights to the drug, conducted a Phase 2 clinical trial of the drug in Alzheimer’s patients and found some benefit. A larger Phase 3 trial, required for Food and Drug Administration approval, is now under way and results are expected later this year.

They also began testing it against Huntington’s, which is marked by a deterioration of mitochondria in brain cells. In a Phase 2 trial, Dr. Kurt Kieburtz of the University of Rochester Medical Center and his colleagues studied the drug in 91 Huntington’s patients over a 90-day period. Half received the drug in three daily doses and half received a placebo. The study was primarily a safety trial and the researchers concluded that the drug posed no untoward risks: About 70% of patients receiving the drug reported adverse side effects, but so did 80% of those receiving a placebo.

The drug produced no benefits on motor function, but it did yield an improvement in a mental test called the Mini-Mental State Examination, in which patients answer questions about what year it is and where they are, count backward, and try to recall words they haver recently heard. Patients receiving the drug showed an average improvement of 0.86 point on the 30-point scale, while those on placebo showed an 0.12-point decline. Kieburtz said he was surprised to see the improvement because the exam is a relatively crude test of mental function.

The trial was sponsored by Medivation and Pfizer, which hope to market the drug under the brand name Dimebon. The company now has a larger trial of 350 Huntington’s patients in progress as a final step toward winning FDA approval.
source: latimesblogs.latimes.com

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Eiger BioPharmaceuticals Announces Identification of a Novel Class of HCV Inhibitors

Last Updated on Thursday, 6 May 2010 03:10 Written by Editor Thursday, 6 May 2010 03:10

PALO ALTO, Calif., Jan. 20, 2010 /PRNewswire/ — Eiger BioPharmaceuticals, Inc., a biotechnology company developing antiviral therapies, announced today the publication of research from the labs of Stanford scientist and Eiger Founder, Dr. Jeffrey Glenn, M.D., Ph.D. and colleagues entitled, “Identification of a Novel Class of HCV Inhibitors”.  Published in the January 20th edition of Science and Translational Medicine, the research validates a domain, termed 4BAH2, within the non-structural protein (NS4B) of the HCV genome, as essential for HCV replication and describes the development of a high-throughput screen leading to the identification of small molecule inhibitors of 4BAH2.

“The 4BAH2 is the second new domain within NS4B now proven necessary and essential for HCV replication, and which has been shown to be susceptible to pharmacologic inhibition.  Eiger is developing small molecule inhibitors of both NS4B-RNA binding and small molecule inhibitors of NS4B-AH2, each of which has significant activity alone and significant synergy when combined,” said David Cory, President and CEO of Eiger. “Inhibiting these NS4B functions represents an exciting new approach toward developing new classes of virus-specific agents to treat HCV.”

“The discovery of a new class of HCV inhibitors against a novel target that is described in this paper paves the way for the development of novel anti-HCV strategies. This is of particular benefit because, like AIDS and tuberculosis, future effective therapy for HCV is expected to require a cocktail of several independent classes of drugs, each designed against a different viral target.  As such, the types of inhibitors described in this paper represent ideal components of future anti-HCV drug cocktails,” said Jeffrey Glenn, M.D., Ph.D., Founder of Eiger.  ”I am particularly excited to be working with the Eiger team because they have proven their ability to rapidly develop potent derivatives of the initial compounds described in my lab, and to efficiently move leads to the clinic.”

About 4BAH2

Representing a second target of interest to Eiger within NS4B, 4BAH2 has been genetically-validated and consists of a conserved amphipathic helix (AH) essential for viral genome replication. 4BAH2 has a dramatic specific biochemical activity of promoting the aggregation of lipid vesicles, with likely relevance to the establishment of the membranous web, the site of HCV replication.  This biochemical activity was leveraged into a new high throughput screening assay for pharmacologic inhibitors of 4BAH2 function.  Analysis of these inhibitors reveals a mechanism of action involving inhibition of 4BAH2 induced vesicle aggregation.  Eiger has developed a next generation series of potent 4BAH2 inhibitors that are highly active as single agents against HCV, and highly synergistic when combined with the NS4B-RNA inhibitor, clemizole.

About Eiger BioPharmaceuticals, Inc. www.eigerbio.com

Eiger is focused on the discovery and development of new antiviral agents against novel targets for the treatment of hepatitis virus infections. Eiger’s pipeline includes repurposed clinical stage therapeutic agents as well as preclinical NCEs from discovery that exhibit antiviral activity against Hepatitis C, Hepatitis D, and other viruses. Eiger investors include InterWest Partners www.interwest.com and Vivo Ventures www.vivoventures.com.

source: prnewswire.com

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Fast Forward, Juvenile Diabetes Research Foundation and Axxam SpA Join Forces to Accelerate Development of Treatments for Multiple Sclerosis and Type 1 Diabetes

Last Updated on Thursday, 6 May 2010 02:46 Written by Editor Thursday, 6 May 2010 02:46

NEW YORK and MILAN, Italy, Jan. 19 /PRNewswire-USNewswire/ — Fast Forward, LLC, the commercial drug development arm of the National Multiple Sclerosis Society, and the Juvenile Diabetes Research Foundation (JDRF), the leader in research leading to a cure for type 1 diabetes in the world today announced a collaborative partnership with Axxam SpA — a leading company in conducting early-stage discovery research programs for the life science industry — to develop new treatments for two autoimmune diseases, multiple sclerosis (MS) and type 1 diabetes (T1D).

Under the terms of the agreement, Axxam will screen its extensive chemical library to identify compounds that can target specific ion channels in the immune system. Ion channels are tiny pores on the surface of immune cells that control the influx of charged particles and allow the cells to become activated to perform their natural surveillance and protection functions.  Recent studies have found that immune cells in MS and T1D contain high levels of a specific ion channel, Kv1.3, and that the hyperactivity of this channel contributes to the dysfunction of the immune system in MS and T1D.  If the initial research is successful, Axxam will have identified compounds that modulate Kv1.3 ion channel activities, and these will be further developed by the company as potential therapies for MS and T1D.

The agreement with Axxam is the first of its kind between cross-disciplinary patient advocacy organizations and represents a new frontier in which groups such as JDRF and Fast Forward ally to lessen the risk of drug discovery and accelerate the development of new therapies that can impact multi-disorders.  ”We are pleased to partner with Axxam and JDRF to advance the development of new treatments for T1D and MS,” said Dr. Timothy Coetzee, President of Fast Forward.  Adds Dr. Coetzee, “People with MS and T1D need more treatment options and the approach taken by Axxam holds great promise for both diseases.”

“Our partnership with Fast Forward and Axxam opens exciting new avenues for JDRF to speed the translation of basic research into drugs and treatments for type 1 diabetes,” said Alan J. Lewis, PhD, President and Chief Executive Officer of JDRF.  “Research into the Kv1.3 ion channel has the potential to negate the autoimmune process causing type 1 diabetes and multiple sclerosis, which must be addressed to cure these diseases.”

“It’s rewarding for Axxam to be working with two world class non-profits dedicated to speeding new therapies to their constituencies,” said  Dr. Stefan Lohmer, Ph.D., Chairman and Chief Executive Officer of Axxam. “This collaboration recognizes the quality of our research in the challenging ion channels field and we hope to be on the cusp for developing potential new therapies for both type 1 diabetes and multiple sclerosis.”

About JDRF:

JDRF is the worldwide leader for research to cure type 1 diabetes.  It sets the global agenda for diabetes research, and is the largest charitable funder and advocate of diabetes science worldwide.

The mission of JDRF is to find a cure for diabetes and its complications through the support of research.  Type 1 diabetes is an autoimmune disease that strikes children and adults suddenly, and can be fatal.  Until a cure is found, people with type 1 diabetes have to test their blood sugar and give themselves insulin injections multiple times or use a pump — each day, every day of their lives.  And even with that intensive care, insulin is not a cure for diabetes, nor does it prevent its eventual and devastating complications, which may include kidney failure, blindness, heart disease, stroke, and amputation.

Since its founding in 1970 by parents of children with type 1 diabetes, JDRF has awarded more than $1.4 billion to diabetes research, including $101 million in FY2009.  In FY2009, JDRF funded research projects in 22 countries throughout the world, including more than 40 human clinical trials.

About Fast Forward, LLC

Fast Forward, LLC is a nonprofit organization and critical initiative established by the National Multiple Sclerosis Society in order to accelerate the development of treatments for MS. Fast Forward will accomplish its mission by connecting university-based MS research with private-sector drug development and by funding small biotechnology/pharmaceutical companies to develop innovative new MS therapies and repurpose FDA-approved drugs as new treatments for MS. For more information visit: www.fastforward.org

About MS and the National Multiple Sclerosis Society

MS is a chronic, unpredictable neurological disease that affects the central nervous system. It is thought to be an autoimmune disorder, meaning the immune system incorrectly attacks healthy tissue. Symptoms may be mild, such as numbness in the limbs, or severe, such as paralysis or loss of vision. These problems may be permanent or may come and go. The National MS Society addresses the challenges of each person affected by MS by funding cutting-edge research, driving change through advocacy, facilitating professional education, collaborating with MS organizations around the world, and providing programs and services designed to help people with MS and their families move their lives forward. The Society is dedicated to achieving a world free of MS. Join the movement at  www.nationalMSsociety.org

About Axxam SpA

Axxam is a discovery company focused on research programs for different applications in the life science industry.  They are a privately owned biotech firm based at the San Raffaele Biomedical Science Park in Milan (Italy), with a team of about 60 highly skilled qualified people. Axxam began operations as an independent and privately owned company in November 2001, but its roots are built upon years of experience as part of the Bayer HealthCare, Research and Development organization.  The company performs a wide range of activities including assay development, high-throughput screening, compound profiling and hits to leads testing. In addition, Axxam conducts several discovery programs for selected targets which are carried out in partnership with other companies or non-profit organizations. For more information, please visit  www.axxam.com.

SOURCE Juvenile Diabetes Research Foundation

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Compounds that help protect nerve cells discovered by Duke team

Last Updated on Thursday, 6 May 2010 02:45 Written by Editor Thursday, 6 May 2010 02:45

DURHAM, N.C. – Scientists at Duke University Medical Center have found some compounds that improve a cell’s ability to properly “fold” proteins and could lead to promising drugs for degenerative nerve diseases, including Huntington’s disease, Alzheimer’s disease and Parkinson’s disease.

Misfolded proteins in nerve cells (neurons) are a common factor in all of these diseases. The Duke team has identified many new chemicals that activate a master regulator to increase the supply of “protein chaperone” molecules that help fold proteins properly.

The scientists further explored one of the candidate molecules to activate the master regulator of chaperone gene expression, Heat Shock Factor 1 (HSF1), to learn whether it would work in model systems of Huntington’s disease, a devastating neurodegenerative disease of protein misfolding.

They were able to show that the molecule stimulated protein chaperones in cells and in an animal system. The damage to early-state rat neurons was much lower in cells pre-treated with the HSF1 activator, and damage to the neurons of fruit flies that had a Huntington’s-like disorder was also greatly reduced.

Previous studies suggested that elevating the abundance of protein chaperones is effective in treating cell and animal models of Huntington’s and Parkinson’s diseases. This work provides a new approach to address the root cause of these diseases — protein misfolding. Earlier attempts had used heat shock and other approaches that stress a nerve cell in order to produce more chaperone molecules, but at a cost of damaging the cell to save it.

“The advantage of our screen is that it identifies molecules that can elevate the levels of chaperones without inducing cellular stress and that don’t inhibit a key protein chaperone called Hsp90 that is needed for cells to function normally,” said senior author Dennis J. Thiele, Ph.D., Professor of Pharmacology and Cancer Biology. “We found a creative way to identify new molecules that can activate the body’s natural protein folding machinery.”

The research was published in the Jan. 19 online issue of PLoS Biology.

Lead author Daniel Neef, Ph.D., says they used genetically altered yeast to find compounds that might aid chaperone development. The scientists took yeast with a deleted HSF1 (master regulator) gene and inserted the related human HSF1 gene. These yeast, however, still weren’t able to activate human HSF1 on their own, and in effect, died. They needed an additional molecule to make human HSF1 become active.

The team put these “humanized yeasts” into wells and started testing compounds that would provide the missing link. In several of the wells, if the compound worked, the yeast started multiplying. “Out of over 12,000 compounds tested from chemical libraries, about 50 compounds worked,” Neef said. The team decided to explore one of these compounds (HSF1A) in further experiments.

“The humanized yeast-based screening results in our study provide a way to identify new classes of small molecules, small enough to penetrate the blood-brain barrier to work in neurons, in flies as well as in humans,” Thiele said. “These small molecules may be effective therapies in neurodegenerative diseases caused by protein conformational disorders such as Huntington’s, Alzheimer’s and Parkinson’s disease.”

The scientists found that HSF1A could stimulate more protein chaperones and reduce the protein misfolding. They showed that adding a small amount of HSF1A to the developing rat neurons kept the proteins dissolved throughout the cell, rather than clumping visibly as speckled areas (as seen under microscopes).

“We enhanced the cells’ viability by four or five times by pre-treating them with this molecule,” Neef said. “Otherwise, the cells would have died.”

They used fruit flies with Huntington’s disease for experiments to prove that the principle would work in an animal. Adding HSF1A to the fly’s food produced more chaperone molecules in their neurons. This suggests that the molecule could travel from the fly’s stomach into its circulation and cross a barrier to the fly brain.

In the key experiment, the Huntington’s disease flies received either their usual food or food plus HSF1A. Those with untreated food developed eyes with dying photoreceptor neurons and lacking the normal red color. Those that ate HSF1A went on to have normal-colored eyes, indicating a repair had taken place, just by eating food laced with the promising compound.

source: eurekalert.org

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Open access drug discovery database launches with half a million compounds

Last Updated on Thursday, 6 May 2010 01:48 Written by Editor Thursday, 6 May 2010 01:48

Drug delivery capsules

ChEMBLdb, a vast online database of information on the properties and activities of drugs and drug-like small molecules and their targets, launches today with information on over half a million compounds. The data lie at the heart of translating information from the human genome into successful new drugs in the clinic.

The database is hosted by the European Molecular Biology Laboratory’s European Bioinformatics Institute (EMBL-EBI). It was transferred from biotech firm Galapagos NV in July 2008 through a £4.7 million Strategic Award from the Wellcome Trust.

ChEMBLdb is a unique resource because of its focus on drug discovery and its size: information on an additional 100 000 compounds has been added to the database for its launch, taking the number of small molecules to over 520 000, and it now contains over 2.4 million records of their effects on biological systems. The data include information about how small molecules bind to their targets, how these compounds affect cells and whole organisms, and information on the molecules’ absorption, distribution, metabolism, excretion and toxicity.

Dr John Overington, leader of the ChEMBL team at EMBL-EBI, said: “We hope ChEMBLdb will assist the translation of genomic-based insights into innovative drug therapies. We are pleased that there has already been big demand for ChEMBLdb data – not only from large pharmaceutical companies but also from academic institutions and small companies who will particularly benefit from free access to the data.”

The human genome sequence provided a molecular ‘parts list’ for a human being, comprising all the genes and proteins that are encoded by our genetic blueprint. In order to develop new medicines, it is important to catalogue how each of these ‘parts’ interacts with drugs and drug-like molecules. ChEMBLdb brings together information from the interface of the genome with chemistry into a set of ‘chemogenomic’ databases that can be used to help determine whether a particular molecule has the right properties to make an effective drug.

Professor Janet Thornton, Director of EMBL-EBI, said: “We are delighted to augment the biological data archived and served from EMBL-EBI with the ChEMBLdb resource. The database adds an important new capability to address the needs of the pharmaceutical and biotechnology industries, and provide the academic chemical biology communities with previously inaccessible data.”

Dr Alan Schafer, Director of Science Funding at the Wellcome Trust, said: “This unprecedented transfer of pharmaceutical data resources from the private sector to the public domain should have the greatest impact on researchers in academia and in small companies on limited budgets. ChEMBLdb will be a major resource of information for driving forward medicinal chemistry and drug development in the UK and internationally.”

The launch of ChEMBLdb is accompanied by the release of Kinase SARfari, an integrated resource of sequence, compound and screening data from a variety of sources for the protein kinases, a key family for drug discovery.

Image: Drug delivery capsules. Credit: Anna Tanczos, Wellcome Images

Contact

Craig Brierley
Senior Media Officer
Wellcome Trust
T +44 (0)20 7611 7329
E c.brierley@wellcome.ac.uk

Louisa Wright
Outreach Programme Project Leader
EMBL-EBI
T +44 (0)1223 494665
E louisa@ebi.ac.uk

Katrina Pavelin
Scientific Outreach Officer
EMBL-EBI
T +44 (0)1223 494452
E katrina@ebi.ac.uk

source; wellcome.ac.uk

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Kansas studies plants’ medicinal values

Last Updated on Thursday, 6 May 2010 11:55 Written by Editor Thursday, 6 May 2010 11:55

The snow on the ground keeps Lauren Ashman inside entering data about native plant species instead of out in the field. This is the dirty work of the $5 million Native Medicinal Plant Research Program.

Along with data entry, Ashman, junior from St. Louis, Mo., works on drying and putting the 10- to 20-pound bags of plant species in alphabetical order. Only then are they ready to go to the High Throughput Screening Lab at the Structural Biology Center on West Campus.

The project started Nov. 11, 2009, when two faculty members at the University received money from Heartland Plant Innovations, Inc., to study plants in the Kansas area. The Heartland Plant Innovations, Inc., branches from the Kansas Bioscience Authority, a center aimed at advancing Kansas’ leadership in bioscience.

Barbara Timmermann, a university distinguished professor in the Medicinal Chemistry Department, and Kelly Kindscher, associate scientist at the Kansas Biological Survey, will lead the research during the next five years.

In that time, the goal of the research is to gain credible findings and data on the local plants so various food and drug industries can understand the plants’ capabilities.

“There is a big interest in bringing business to Kansas,” Kindscher said. “The findings of this project could bring in herbal product to cosmetic or pet food companies.”

Hayley Kilroy, graduate student from Cleveland, Ohio, said Native Americans and pioneers once used the native plants for medicinal purposes. Now that the University is looking at the plants for those uses again, it will help conserve the biodiversity of Kansas.

“Conservation is important,” Kilroy said, “but when you can make money through conserving, there is a lot more incentive for it.”

The researchers face a long process of identifying, collecting and studying the plants for their medicinal uses and effectiveness. Kindscher and Timmermann said they were looking at hiring up to 12 new employees to handle maps, data and research.

Kindscher and students collected plants this summer from Douglas County and several areas of Western Kansas. The plants now sit in a lab waiting to be dried and cataloged.

“We go out in teams and gather all our plant material,” Kindscher said. “I love the field work.”

In previous years, Kindscher and others collected plants for the main purpose of researching and replanting native prairie. But the grant has narrowed their focus to the medicinal uses of specific plants.

Quinn Long, doctoral student from Franklin County, Mo., said the team would collect multiple samples from different areas for each species. Then they can study how differences in location change what chemical compounds are present in a plant. Long said different stresses, such as drought, could increase medicinal compound.

Because the program started in late fall, Timmermann’s lab doesn’t have as many samples to study. However, that will change as spring arrives and more plants can be collected.

“It would be great if we found the next best cure,” Kindscher said. “But we are not directly focusing on that or the money.”

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Sleep with the Fishes Zebrafish larvae are a surprisingly compatible stand-in for humans as researchers test the next generation of insomnia drugs.

Last Updated on Thursday, 6 May 2010 11:44 Written by Editor Thursday, 6 May 2010 11:44

There’s a new guinea pig in the search for sleep-related drugs: the zebrafish. Researchers at Harvard University have developed a screening tool that tests the effects of thousands of compounds on zebrafish behavior in an effort to discover new pathways that govern sleep. The research, published this week in the journal Science, may result in new drugs to treat insomnia and other sleep-related disorders.

Sleepy head: Harvard scientists are using zebrafish as a model to find drug candidates for insomnia and other sleep disorders. Pictured above is the head portion of a zebrafish larva. The zebrafish brain is labeled in green.
Credit: Albert Pan and Alexander Schier

Alexander Schier and his colleagues at Harvard developed an automated system to assess 60,000 distinct sleep-related behaviors in zebrafish, a tropical fish often used in scientific research. After screening 5,600 small molecules on the larvae, the team discovered 463 significant sleep-altering compounds, many of which have been known to have similar effects in humans.

“We didn’t expect as much conservation of the effects of drugs between humans and zebrafish,” says Schier, professor of molecular and cellular biology. “This was a proof of principle that many of the pathways found in humans are conserved in fish.”

Schier says such behavioral similarities may make zebrafish an ideal model for studying how and why humans sleep, mysteries that are largely unsolved. It’s still unclear what molecular mechanisms control sleep and wakefulness. Pinpointing these pathways, and finding drugs to block or promote them, is a major focus for many pharmaceutical companies–sleep drugs generate $7 billion in annual profits in the United States. However, the drug development process is tedious and expensive. Schier believes that testing drug candidates in zebrafish could be a cheap and straightforward alternative to conventional drug screening.

Typically, to test a drug, researchers first study its effects in cultured cells, looking to see if the drug binds successfully to a target receptor or molecule. They then advance the drug to animal experiments, testing behavioral effects in live subjects. But drugs that have certain effects in cultured cells often have unexpected side effects–or no effect–in a live animal.

“The advantage of zebrafish is that you can keep large numbers of animals in a very small space, and raise many, many animals relatively cheaply,” says Schier. Unlike flies and worms, which are often used in the early stages of pharmaceutical research, fish are vertebrates. “Much can be found in zebrafish that is relevant to mammals,” he says.
To screen the drugs, researchers pipetted single zebrafish larvae into a tiny well of a 96-well tray. Each well was injected with a drug, with one drug tested on 10 different larvae. They placed the tray in a recording chamber with infrared and white LED lights and a camera connected to computer software. After lining the tray up with a corresponding grid on the computer screen, researchers programmed the timing of light to simulate day and night. The camera recorded each fish’s activity over two days, and video tracking software plotted out each fish’s movements per second.

Z’s for zebrafish: Zebrafish larvae (above) are naturally transparent. Scientists hope to one day study the effects of sleep drugs on the brain and spinal cord, which can be seen in the image above as a long white structure stretching left to right.
Credit: Albert Pan and Alexander Schier

Using clustering algorithms, Schier and his colleagues grouped fish into 60,000 distinct behavioral profiles, depending on various constraints. “When you turn off the light, how often are they active? When they are inactive, how long? That’s what we observe in the fish,” says Schier. “You can measure many different parameters, and that allows you to profile different drugs.”

Anti-inflammatories, such as cytokines, nonsteroidal anti-inflammatory drugs, and cyclosporine, had a surprising effect. Normally, these drugs induce sleep when taken to combat infection such as the flu. However, Schier found that when given to normal, healthy zebrafish, these compounds, or immunomodulators, made fish more active during the day.

“In disease, immunomodulators have been implicated in sleep,” says Schier. “We propose that maybe there’s some baseline function for these immunomodulators during normal sleep and wake cycles.”

Such findings could help researchers identify new molecular players involved in sleep and wakefulness. Irina Zhdanova, associate professor of anatomy and neurobiology at Boston University Medical School, studies the physiological mechanisms of circadian rhythms and sleep in zebrafish. Zhdanova says there are many sleep-related drugs on the market with substantial side effects; these effects might be avoided with better screening tools.

“The huge scope of drugs tested [by Schier's group] shows that zebrafish-based tests can be effectively used to at least prescreen multiple classes of existing drugs and new candidate substances,” says Zhdanova. “[That is] certainly very helpful.”

In the future, Schier says, zebrafish could also be used as a model for testing drugs for human psychiatric diseases like schizophrenia and autism. The idea is to identify genes associated with the human disease, and try to engineer the same genetic defect in zebrafish. Researchers could then look for certain behavioral changes as a result, such as a fish’s sensitivity to touch, or its reaction to visual cues.

“Hopefully there would be a connection between the gene affected, and change in behavior, and one would try to correct the change in behavior by adding particular drugs,” says Schier. “That’s a bit science fiction at the moment, but it is possible.”

source:technologyreview.com

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Hunt for Dioxin Substitutes to Fight Autoimmune Diseases

Last Updated on Thursday, 6 May 2010 11:41 Written by Editor Thursday, 6 May 2010 11:41

(HealthNewsDigest.com) – CORVALLIS, Ore. – Scientists at Oregon State University are hunting for substitute chemicals for a toxic dioxin to fight diseases that are triggered by haywire immune systems attacking the body.

The dioxin, known as TCDD, has been shown to suppress the immune system in animals and prevent type 1 diabetes in mice. OSU researchers hypothesize that it could do the same in people. But they aren’t considering it as a treatment because it has produced bad side effects in animals and can cause chloracne, a disfiguring skin disease in humans.

Instead, they’re looking for safer alternatives that would function like TCDD, which is perhaps best-known for its presence in the jungle-decimating Agent Orange herbicide used during the Vietnam War.

If successful, the chemicals might be able to prevent and treat autoimmune diseases like rheumatoid arthritis, multiple sclerosis, psoriasis and type 1 diabetes.

“Immunosuppressive drugs are already used to treat these diseases, but they can create their own problems,” said Nancy Kerkvliet, an OSU immunotoxicologist who is helping conduct the research. “Consequently, the new way of thinking is to use a mixture of drugs at lower doses to reduce the side effects caused by higher dosages of individual drugs. Through our research, we’re hoping to discover new drugs that will expand the choices of drugs that can be used.”

To help with that effort, the American Recovery and Reinvestment Act of 2009 provided Kerkvliet and her team with $1.8 million.

Kerkvliet has been studying dioxins for three decades. She published a paper last year in the journal Immunotherapy that showed that in mice TCDD can prevent type 1 diabetes, which occurs when the immune system attacks the pancreas and kills the cells that produce insulin. The mice used in the study develop type 1 diabetes spontaneously because of genetic defects in their immune system. However, of the 12 mice that were treated with TCDD, none developed the disease. Eight of the 11 mice that weren’t treated with it developed diabetes by 28 weeks of age.

Kerkvliet said that TCDD’s effect on the immune system of mice works like this: First, it binds to a protein called the aryl hydrocarbon receptor (AhR) found inside a cell. The united TCDD and AhR then pass into the nucleus, latch onto DNA and turn certain genes on or off. Kerkvliet’s research suggests that this process produces regulatory T cells, which then shut down the immune system’s response. This then suppresses the development of diabetes, she said.

To help her find alternatives for TCDD, cancer biologist Siva Kolluri and his crew are screening 50,000 chemical compounds in search of ones that will bind to AhR and induce regulatory T cells. So far, they’ve tested about 5,000 in cell-based assays for their ability to activate AhR, Kolluri said.

“There have been some promising hits,” he said. “We need to make sure that they work only through this receptor. We also have to make sure they’re not toxic. We don’t want them to have any of the bad effects that TCDD has.”

Later, Kerkvliet and her team will test the compounds in mice to see if they prevent type 1 diabetes. If they do, Kerkvliet believes that it would be likely that they would also fight other autoimmune diseases because most of these diseases are also controlled by regulatory T cells. Of course, any chemicals that are successful in treating laboratory animals would eventually have to be studied in humans to see if the effects are the same.

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Science & Health > Chemistry > Zebrafish point the way Screening method finds new roles for drugs in sleeping, waking

Last Updated on Thursday, 6 May 2010 11:33 Written by Editor Thursday, 6 May 2010 11:33

A robust new technique for screening drugs’ effects on zebrafish behavior is pointing Harvard University scientists toward unexpected compounds and pathways that may govern sleep and wakefulness in humans.Among the scientists’ more intriguing findings, described in the journal Science, are that various anti-inflammatory agents in the immune system, long known to induce sleep during infection, may also shape normal sleep/wake cycles.

The new research identifies several compounds with surprising effects on sleep and wakefulness in zebrafish. But it also suggests that despite the evolutionary gap between zebrafish and mammals, they may be strikingly similar in the neurochemistry underlying their rest/wake cycles, meaning that these same compounds may prove effective in people.

“Many current drug discovery efforts rely on screening conducted outside the body,” said Alexander F. Schier, professor of molecular and cellular biology at Harvard. “Although such screens can be successful, they cannot recreate the complex neuroscience of entire organisms. These limitations are particularly acute for behavior-altering drugs, because brain activity cannot be modeled in a Petri dish or test tube.”

Together with postdoctoral fellows Jason Rihel and David Prober, Schier and other collaborators used their automated screening technique to monitor sleep and wakefulness in zebrafish for two days following administration of 5,600 compounds, creating more than 60,000 distinct behavioral profiles. By applying clustering algorithms to organize the molecules, the researchers identified 463 drug candidates that significantly altered rest and wakefulness, many of which had not previously been known to have such effects.

“For instance, we found that a diverse set of anti-inflammatory compounds increased wakefulness during the day, with much less effect at night,” Schier said. “Although these compounds have long been known to promote sleep during infection, this is an indication that the molecules that regulate the immune system may also play a role in setting normal daytime activity levels.”

Anti-inflammatory agents found to affect sleep/wake cycles included cytokines, nonsteroidal anti-inflammatory drugs, and the immunosuppressant cyclosporine. Schier and colleagues also found calcium channel inhibitors that increased rest with minimal effects on waking behavior and a class of potassium channel blockers found in a wide variety of drugs — including antimalarials, antipsychotics, and antihistamines — that selectively increased wakefulness at night without affecting total rest.

“Behavioral profiling reveals nuanced relationships between drugs and their targets,” Schier said. “It can characterize large classes of compounds and reveal differences in effectiveness, potential side effects, and combinatorial properties that might not otherwise be detected.”

Schier and his colleagues plan to expand their zebrafish screening to include many more uncharacterized compounds and to assay behaviors that, in humans, are associated with psychiatric disorders.

Schier’s co-authors on the Science paper are Jason Rihel, David A. Prober, Anthony Arvanites, Kelvin Lam, Steven Zimmerman, Sumin Jang, and Lee L. Rubin, all at Harvard; Stephen J. Haggerty of the Broad Institute of Harvard and MIT and Massachusetts General Hospital (MGH); David Kokel of MGH; and Randall T. Peterson of the Broad Institute, MGH, and Harvard Medical School.

The work was funded by the Life Sciences Research Foundation, the Helen Hay Whitney Foundation, the National Institutes of Health, the Stanley Medical Research Institute, the Harvard Stem Cell Institute, and the McKnight Endowment Fund for Neuroscience.

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