Features | Partner Sites | Information | LinkXpress
Sign In
GLOBETECH MEDIA
GLOBETECH PUBLISHING LLC
GLOBETECH PUBLISHING LLC

Combination Drug Screening Strategy Identifies Obesity-Diabetes Treatment Target

By BiotechDaily International staff writers
Posted on 02 Jan 2014
Image: As proof of the power of their new screening strategy, researchers at The Scripps Research Institute used the method to identify a compound that shows promise for treating obesity-linked diabetes. This image shows a structure identified as a target for obesity-diabetes (human Ces3), superimposed on a field of human fat cells with their lipids stained with a fluorescent dye (Photo courtesy of the Scripps Research Institute).
Image: As proof of the power of their new screening strategy, researchers at The Scripps Research Institute used the method to identify a compound that shows promise for treating obesity-linked diabetes. This image shows a structure identified as a target for obesity-diabetes (human Ces3), superimposed on a field of human fat cells with their lipids stained with a fluorescent dye (Photo courtesy of the Scripps Research Institute).
A drug discovery strategy that combined phenotypic screening with a target-identification approach was used to identify a novel drug target that, when treated, relieved symptoms of metabolic disease in mouse models.

Phenotypic screening, which tests candidate drug compounds for their ability to produce a desired effect directly on living cells, has largely been replaced by high throughput target-based screening, which assays candidate compounds against large numbers of biochemical reactions in microarrays. However, candidate drugs selected by target-based screening often fail when tested in cellular settings.

To improve chances of selecting successful drug candidates investigators at the Scripps Research Institute (La Jolla, CA, USA) have combined phenotypic screening of a directed small-molecule library with competitive activity-based protein profiling to map and functionally characterize the targets of screening hits.

They reported in the December 22, 2013, online edition of the journal Nature Chemical Biology that they had used this combined strategy to identify carboxylesterase 3 (Ces3) as a primary molecular target of bioactive compounds that promote lipid storage in adipocytes. Ces 3 was known previously to be a member of a large multigene family. The enzymes encoded by these genes had been shown to be responsible for the hydrolysis of ester- and amide-bond-containing drugs such as cocaine and heroin. They also hydrolyzed long-chain fatty acid esters and thioesters. The specific function of this enzyme had not yet been determined; however, it was speculated that carboxylesterases played a role in lipid metabolism and/or the blood–brain barrier system. The CES3 gene is expressed in several tissues, particularly in colon, trachea, and brain, and the protein participates in colon and neural drug metabolism.

The Scripps investigators reported that Ces3 activity was markedly elevated during adipocyte differentiation. They treated two mouse models of obesity-diabetes with a Ces3 inhibitor and found that this drug (WWL113) corrected multiple features of metabolic syndrome, illustrating the power of the described strategy to accelerate the identification and pharmacologic validation of new therapeutic targets.

"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. This integrated strategy we have 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 Dr. Enrique Saez, associate professor of chemical physiology at The Scripps Research Institute.

"The [WWL113] treated animals showed resistance to weight gain—they were not putting on as much weight as the controls," said Dr. Saez. "Their blood biochemistry also was getting normalized; their glucose, triglyceride, and cholesterol levels were coming down towards normal levels."

Related Links:

The Scripps Research Institute



Channels

Genomics/Proteomics

view channel
Image: The photo shows a mouse pancreatic islet as seen by light microscopy. Beta cells can be recognized by the green insulin staining. Glucagon is labeled in red and the nuclei in blue (Photo courtesy of Wikimedia Commons).

Regenerative Potential Is a Trait of Mature Tissues, Not an Innate Feature of Newly Born Cells

Diabetes researchers have found that the ability of insulin-producing beta cells to replicate and respond to elevated glucose concentrations is absent in very young animals and does not appear until after weaning.... Read more

Biochemistry

view channel
Image:  Model depiction of a novel cellular mechanism by which regulation of cryptochromes Cry1 and Cry2 enables coordination of a protective transcriptional response to DNA damage caused by genotoxic stress (Photo courtesy of the journal eLife, March 2015, Papp SJ, Huber AL, et al.).

Two Proteins Critical for Circadian Cycles Protect Cells from Mutations

Scientists have discovered that two proteins critical for maintaining healthy day-night cycles also have an unexpected role in DNA repair and protecting cells against genetic mutations that could lead... Read more

Business

view channel

Roche Acquires Signature Diagnostics to Advance Translational Research

Roche (Basel, Switzerland) will advance translational research for next generation sequencing (NGS) diagnostics by leveraging the unique expertise of Signature Diagnostics AG (Potsdam, Germany) in biobanks and development of novel NGS diagnostic assays. Signature Diagnostics is a privately held translational oncology... Read more
 
Copyright © 2000-2015 Globetech Media. All rights reserved.