Corporate Banner
Satellite Banner
Technology
Networks
Scientific Communities
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Innovative Screening Strategy Swiftly Uncovers New Drug Candidates, New Biology

Published: Tuesday, December 24, 2013
Last Updated: Tuesday, December 24, 2013
Bookmark and Share
Method has been utilised to identify compound with promise for obesity-linked diabetes.

Scientists at The Scripps Research Institute (TSRI) have demonstrated a drug-discovery strategy with a double payoff—it enables the rapid selection of chemical compounds that have a desired effect on cells and also highlights how the compounds work.

To illustrate the power of the innovative technique, the TSRI researchers used it to identify a compound that shows promise for treating obesity-linked diabetes. At the same time, they were able to identify the fat-cell enzyme that the compound inhibits—an enzyme that has not yet been a focus of diabetes drug development.

“This integrated strategy we’ve developed has the potential to accelerate the discovery of important biological pathways and may lead to faster development of new drugs for multiple diseases,” said TSRI Associate Professor Enrique Saez.

Saez and his colleague Benjamin F. Cravatt, chair of TSRI’s Department of Chemical Physiology, were the senior authors of the new study, which is reported  December 22, 2013 in an advance online issue of Nature Chemical Biology.

Facilitating Drug Discovery
The new strategy has great potential to streamline drug discovery, a process whose importance to human health can hardly be overemphasized.

Typically, pharmaceutical scientists start the discovery process by “screening” large libraries of chemical compounds in search of one or a few that might treat disease. The dominant strategy of recent decades has been to screen compounds for a specific activity against a known target, for example, inhibiting the function of a certain enzyme thought to be critical for the disease in question. A key advantage of this “target-based” screening is that it uses biochemical tests that can be done relatively simply in a test-tube—or rather, in a large array of tiny test tubes via automated, rapid screening systems that sort through hundreds of thousands of different compounds.

Target-based screening has enabled scientists to discover many useful new drugs, but some wonder whether this basic discovery strategy has already taken all the “low hanging fruit.” In recent years, compounds selected with target-based in vitro tests have seemed to be failing increasingly often when tested in the more realistic biological environments of cells and animals.

An older strategy, “phenotypic” screening, avoids much of this problem by testing compounds for their ability to produce a desired effect directly on living cells. Unfortunately, such cell-based tests often leave open the question of how a useful compound works. “If you don’t know what its relevant molecular target is, then developing that compound into a drug—optimizing its potency, its selectivity, its half-life in the bloodstream and so on—is going to be difficult,” said Saez.

Identifying the molecular targets of compounds selected by phenotypic screens is typically burdensome and time-consuming. But in their new study, Saez, Cravatt and their colleagues were able to speed up the process dramatically. Indeed, their combined phenotypic screening and target-identification approach enabled them to quickly discover, characterize and carry out preclinical tests of a potential new drug for obesity-linked diabetes: a complex metabolic disorder that affects 347 million people worldwide.

A New Diabetes Drug Candidate, Plus Insights into the Disease
The strategy makes use of the increasing availability of special libraries of related compounds that act as inhibitors of entire enzyme classes. In this case, the researchers used a set of compounds, recently synthesized by Cravatt’s laboratory, that tend to inhibit serine hydrolases—a vast enzyme family whose members participate in most biological processes in mammals.

The scientists started with a phenotypic screen, testing their library of compounds for the ability to make young fat cells mature faster and store more fat. Better fat storage means that less fat leaks from fat cells into the liver, muscles and pancreas—a process that frequently occurs with obesity, often interfering with insulin signaling enough to bring on diabetes.

The screen quickly yielded several compounds that had a strong effect in promoting fat-cell fat storage. The researchers then used a method called “activity-based profiling” to identify the fat-cell serine hydrolases that the compounds inhibited most strongly. One of the most potent compounds, WWL113, turned out to work principally by inhibiting Ces3, a serine hydrolase enzyme that scientists have not studied in the context of obesity or diabetes.

The researchers quickly demonstrated WWL113’s effectiveness in two different mouse models of obesity-linked diabetes—one in which the mice are genetically programmed to become obese and diabetic, and another in which normal mice are made obese and diabetic with a high-fat diet. “The treated animals showed resistance to weight gain—they were not putting on as much weight as the controls,” said Saez. “Their blood biochemistry also was getting normalized; their glucose, triglyceride and cholesterol levels were coming down towards normal levels.”

In these mouse tests, WWL113—without any optimization for use as a drug—performed about as well as the FDA-approved diabetes treatment rosiglitazone (Avandia). Notably, the new compound lacked one of the side effects that drugs in rosiglitazone’s class have in mice: the toxic accumulation of lipids in the liver. “Our compound clears lipids from the diabetic mouse liver, whereas rosiglitazone has the opposite effect,” said Saez.

To explore the relevance of these results to humans, the TSRI team worked with collaborating researchers in Australia to test fat samples from obese humans and diabetics. The tests confirmed that the human version of Ces3 also is unusually active in such patients. This suggests that an inhibitor may also work as a diabetes treatment in people.

Saez and his colleagues will next focus on using the new screening strategy to uncover more biological pathways that could yield new mechanisms to develop potential therapies.

Contributors to the study, “Integrated phenotypic and activity-based profiling links Ces3 to obesity and diabetes,” also included first author Eduardo Dominguez, then a postdoctoral fellow in the Saez Laboratory; as well as TSRI’s Andrea Galmozzi, Jae Won Chang, Ku-Lung Hsu, Joanna Pawlak, Weiwei Li, Cristina Godio, Jason Thomas, David Partida, Sherry Niessen and Daniel K. Nomura; and Australian researchers Paul E. O'Brien and Matthew J. Watt of Monash University, and Aaron P. Russell of Deakin University.

The study was funded in part by the National Institutes for Health (DK081003, DK099810), the American Diabetes Association, The McDonald’s Center for Type 2 Diabetes and Obesity, the National Health and Medical Research Council of Australia, the Hewitt Foundation for Medical Research and the Xunta de Galicia, Spain.


Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,500+ scientific posters on ePosters
  • More Than 3,700+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Scientists Make Strides in Therapy Preventing Addiction Relapse
Single Injection of Drug Candidate Prevents Meth Relapse in Animal Models.
Thursday, August 06, 2015
New Antibody Weapons Against Marburg Virus
A study has identified new immune molecules that protect against deadly Marburg virus, a relative of Ebola virus.
Tuesday, June 30, 2015
Team Led by TSRI Scientists Shows AIDS Vaccine Candidate Successfully ‘Primes’ Immune System
New research shows that an experimental vaccine candidate can stimulate immune activity necessary to prevent HIV infection.
Thursday, June 25, 2015
New Details of Potential Alzheimer’s Treatment Uncovered
Scientists from Florida’s Scripps Resarch Institute have uncovered suprising new details of potential Alzheimer’s treatment.
Wednesday, April 29, 2015
Search for Cancer Drug Candidates
Scripps Florida scientists awarded $1.2 million to find drug candidates that could treat a wide range of cancers.
Friday, April 10, 2015
Scripps Florida Scientists Win $1.5 Million Grant to Develop New Cancer Drugs
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have been awarded a $1.5 million grant from the National Institutes of Health (NIH) to develop drug candidates that could treat cancer and neurodegenerative disease.
Tuesday, March 24, 2015
Day-Night Cycles Linked to Mutations
TSRI scientists show that proteins critical in day-night cycles also protect cells from mutations.
Friday, March 13, 2015
More DNA & Extra Copies of Disease Gene in Alzheimer’s Brain Cells
Scientists at The Scripps Research Institute (TSRI) have found diverse genomic changes in single neurons from the brains of Alzheimer’s patients, pointing to an unexpected factor that may underpin the most common form of the disease.
Tuesday, February 24, 2015
Possible Neuron Killing Mechanism Behind Alzheimer’s and Parkinson’s Diseases Discovered
$1.4 million grant will enable team to follow up with search for drug candidates.
Tuesday, February 17, 2015
Microbes Prevent Malnutrition in Fruit Flies—and Maybe Humans, Too
Study shows that microbes play a critical role in nutritional disorders.
Friday, February 13, 2015
New Targets and Test to Develop Treatments for Memory Disorders
The study focuses on kinesin, a molecular motor protein that plays a role in the transport of other proteins throughout a cell.
Thursday, November 13, 2014
MS Drug Candidate Shows Promise for Ulcerative Colitis
Positive new clinical data were released today on a drug candidate for ulcerative colitis that was first discovered and synthesized at The Scripps Research Institute.
Thursday, October 30, 2014
New Technique has Profound Implications for Drug Development
The method, developed by Scripps Research Institute chemists, expands options for making pure batches of ‘one-handed’ molecules.
Thursday, October 30, 2014
Scripps Research Institute Scientists Capture Picture of 'MicroRNA' in Action
The Findings Will Help Guide Drug Design.
Thursday, October 30, 2014
Enzyme Could Help Explain Origins of Life
Mimicking natural evolution in a test tube, scientists at The Scripps Research Institute (TSRI) have devised an enzyme with a unique property that might have been crucial to the origin of life on Earth.
Wednesday, October 29, 2014
Scientific News
The Changing Tides of the In Vitro Diagnostics Market
With the increasing focus in personalized medicine, diagnostics plays a crucial role in patient monitoring.
LaVision BioTec Reports on the Neuro Research on the Human Brain After Trauma
Company reports on the work of Dr Ali Ertürk from the Institute for Stroke and Dementia Research at LMU Munich.
NIH Study Shows No Benefit of Omega-3 Supplements for Cognitive Decline
Research was published in the Journal of the American Medical Association.
Less May Be More in Slowing Cholera Epidemics
Mathematical model shows more cases may be prevented and more lives saved when using one dose of cholera vaccine instead of recommended two doses.
Investigating the Vape
Expert independent review concludes that e-cigarettes have potential to help smokers quit.
NIH Launches Human RSV Study
Study aims to understand infection in healthy adults to aid development of RSV medicines, vaccines.
Researchers Discover Synthesis of a New Nanomaterial
Interdisciplinary team creates biocomposite for first time using physiological conditions.
Poor Survival Rates in Leukemia Linked to Persistent Genetic Mutations
For patients with an often-deadly form of leukemia, new research suggests that lingering cancer-related mutations – detected after initial treatment with chemotherapy – are associated with an increased risk of relapse and poor survival.
Flu Remedies Help Combat E. coli Bacteria
Physiologists from the University of Zurich have now discovered why the intestinal bacterium Escherichia coli (E. coli) multiplies heavily and has an inflammatory effect.
Marijuana Genome Unraveled
A study by Canadian researchers is providing a clearer picture of the evolutionary history and genetic organization of cannabis, a step that could have agricultural, medical and legal implications for this valuable crop.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,500+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,700+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!