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Getting a rise for drug discovery out of simple bakerís yeast
by Jeffrey Bouley  |  Email the author

BETHESDA, Md.óComing out work funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH), researchers have found a tool for identifying potentially useful therapies for Parkinson's disease by turning simple yeast into "virtual army of medicinal chemists capable of rapidly searching for drugs," notes an NIH news release on the findings. Moreover, the same methods may be useful for other disease other than Parkinson's, and for disease other than neurological ones.

In a study, "Rapid Selection of Cyclic Peptides that Reduce alpha-Synuclein Toxicity in Yeast and Animal Models," published online in mid-July by Nature Chemical Biology, the NINDS-funded researchers showed that they can save yeast cells from the toxic effects of a protein implicated in Parkinson's disease by stimulating those yeast cells to make very small proteins called cyclic peptides. Two of the cyclic peptides had a protective effect on the yeast cells and on neurons in an animal model of Parkinson's disease.

"This biological approach to compound development opens up an entirely new direction for drug discovery, not only for Parkinson's disease, but theoretically for any disease where key aspects of the pathology can be reproduced in yeast," says Dr. Margaret Sutherland, a program director at NINDS. "A key step for the future will be to identify the cellular pathways that are affected by these cyclic peptides."

The findings comes out of work at the lab of Dr. Susan Lindquist, Ph.D., a professor of biology at the Massachusetts Institute of Technology (MIT), a member of the Whitehead Institute for Biomedical Research, and a Howard Hughes Medical Institute investigator. Lindquist is also an investigator at the Massachusetts General Hospital/MIT Morris K. Udall Center for Excellence in Parkinson's Research, one of 14 centers funded by NINDS to develop treatment breakthroughs for Parkinson's disease.

Dr. Joshua Kritzer, a chemist and postdoctoral fellow in Lindquist's lab, designed and executed the cyclic peptide strategy and, as he puts it, "We are making the yeast do a ton of work for us. They make the compounds and then they tell us which ones are functional."

Out of a library of 50 million cyclic peptides, only two saved the yeast from alpha-synuclein toxicity, the researchers note. Looking at the Parkinson's work specifically, Kritzer notes that he and colleagues exposed yeast cells to short snippets of DNA that the cells can absorb and use to make cyclic peptides. Then, they turned on the genetic switch that causes the cells to produce toxic levels of alpha-synuclein. If the yeast made cyclic peptides that suppressed alpha-synuclein toxicity, they lived; if not, they died.

As the NINDS notes, this simple assay allowed for the testing of millions of cyclic peptides (CPs) simultaneously in millions of yeast cells. The process is, therefore, "extremely rapid and much less expensive compared to other techniques used to screen large number of chemicals with an eye toward new drugs," notes the NINDS.

As the researchers wrote in their paper, "Hits can be rapidly identified using selections or screens that sort millions of CPs in a single day without expensive robotics. In selections using our yeast synucleinopathy model, we isolated two hits from an original pool of 5 million after only a single round of selection. Although more rounds of selection were not required for selections in the synucleinopathy model, we note that multiple rounds of selection could be performed by pooling colonies and amplifying their plasmids en masse."

"Our technique, which capitalizes on a long line of investigation in my lab, will lead to a whole new way to obtain small molecule tools useful for improving our understanding of disease mechanisms and for developing new therapies," says Lindquist, noting that her lab and others have modeled many human diseases in yeast and in other kinds of cells.

The findings are exciting, notes the NINDS, because of the lack of treatment options for Parkinson's disease. A synthetic precursor of dopamine called L-DOPA, or drugs that mimic dopamine's action, can provide symptomatic relief from Parkinson's disease, but these drugs lose much of their effectiveness in later stages of the disease. Moreover, there is currently no way to substantially slow the progression of Parkinson's disease.

What remains unknown, however, is why the cyclic peptides seem to be protective. They found that the cyclic peptides do not affect a system of transport inside cells known as vesicle trafficking. This came as a surprise, given that alpha-synuclein and other proteins that have been implicated in human Parkinson's disease are believed to play a role in vesicle trafficking. However, the researchers observed that the two peptides share a structure that may hold clues to their targets.The researchers are conducting further experiments to explore how cyclic peptides prevent cell death. They are also adapting their system for making cyclic peptides so that it can be used in other cell types (including human cells) and other diseases.



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