Chemists have devised a new approach to screening cancer drugs that uses gold nanoparticles with red, green and blue outputs provided by fluorescent proteins. Credit: University of Massachusetts Amherst.
Scientists may screen billions of chemical compounds before uncovering the few that effectively treat a disease. But identifying compounds that work is just the first step toward developing a new therapy. Scientists then have to determine exactly how those compounds function.
Different cancer therapies attack cancer cells in distinct ways. For example, some drugs kill cancer cells by causing their outer membranes to rapidly rupture in a process known as necrosis. Others cause more subtle changes to cell membranes, which result in a type of programmed cell death known as apoptosis.
If researchers could distinguish the membrane alterations of chemically treated cancer cells, they could quickly determine how that chemical compound brings about the cells’ death. A new sensor developed by a research team led by Vincent Rotello of the University of Massachusetts Amherst can make these distinctions in minutes. Continue reading “A Bright New Method for Rapidly Screening Cancer Drugs”
The altered AGT protein (red) and peroxisomes (green) appear in different places in untreated cells (top), but they appear together (shown in yellow) in cells treated with DECA (bottom). Credit: Carla Koehler/Reproduced with permission from Proceedings of the National Academy of Sciences USA
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Our cells have organized systems to route newly created proteins to the places where they’re needed to do their jobs. For some people born with a rare and potentially fatal genetic kidney disorder called PH1, a genetically altered form of a particular protein mistakenly ends up in mitochondria instead of in another organelle, the peroxisome. This cellular routing error of the AGT protein results in the harmful buildup of oxalate, which leads to kidney failure and other problems at an early age.
In new work led by UCLA biochemist Carla Koehler , researchers used a robotic screening system to identify a compound that interferes with the delivery of proteins to mitochondria. Koehler’s team showed that adding a small amount of the compound, known as DECA, to cells grown in the laboratory prevented the altered form of the AGT protein from going to the mitochondria and sent it to the peroxisome. The compound also reduced oxalate levels in a cell model of PH1.
The team’s findings suggest that DECA, which is already approved by the Food and Drug Administration for treating certain bacterial infections, could be a promising candidate for treating children affected by PH1. And, Koehler notes, the screening strategy that she and her team used to identify DECA as a potential therapy may help researchers identify other new therapies for the disorder.
This work was funded in part by NIH under grant R01GM061721.
A new compound (chemical structure shown here) blocks the activity of an enzyme involved in glucose regulation.
The discovery of a compound that slows the natural degradation of insulin in mice opens up a new area of investigation in the search for drugs to treat diabetes. The research team, which included David Liu and Alan Saghatelian of Harvard University, Markus Seeliger of Stony Brook University School of Medicine, and Wei-Jen Tang of the University of Chicago focused on insulin-degrading enzyme, or IDE. Using a method called DNA-templated synthesis, the scientists made 14,000 small molecules and found one that bound to the enzyme, suggesting it might modulate the enzyme’s activity. Work in test tubes and in animal models confirmed this—and showed that blocking IDE activity improved insulin levels and glucose tolerance. The researchers also learned that the enzyme is misnamed: In addition to insulin, it degrades two other hormones involved in glucose regulation.
NIGMS’ Peter Preusch says, “This is a very interesting fusion of chemical methods and biology that has uncovered new basic science findings about insulin processing with potential clinical impact.”
This work also was funded by NIH’s National Cancer Institute and the Office of the Director.
Harvard University News Article
Chemistry of Health Booklet
Treating yeast cells with the NAB compound reverses the toxic effects of elevated levels of alpha synuclein protein. Credit: Daniel Tardiff, Whitehead Institute. View larger image
These eye-catching images and the NIGMS-funded research that yielded them were recently featured by NIH Director Francis Collins on his blog. Scientists led by a team at the Whitehead Institute for Biomedical Research engineered yeast to produce too much of a protein, alpha synuclein. In Parkinson’s disease, elevated levels or mutated forms of this protein wreak havoc on the cell. Using the model system, the researchers tested tens of thousands of compounds to identify any that reversed the toxic effects. One did. The compound, abbreviated NAB, worked similarly in an animal model and in rat neurons grown in a lab dish. Collins described the approach as “an innovative strategy for drug hunting that will likely be extended to other conditions.”
Using Model Organisms to Study Health and Disease Fact Sheet
Living Laboratories Chapter from The New Genetics Booklet