Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New method may accelerate drug discovery for difficult diseases like Parkinson's

15.07.2009
Whitehead Institute scientists have developed a rapid, inexpensive drug-screening method that could be used to target diseases that until now have stymied drug developers, such as Parkinson's disease. This technique uses baker's yeast to synthesize and screen the molecules, cutting target discovery and preliminary testing time to a matter of weeks.

The current drug discovery process is arduous, requiring identification of potential drug targets, synthesis of large collections of molecular compounds that might interact effectively with an identified target, screening of compounds with expensive assays and robotics, and defining the compounds' structures largely through trial and error.

At the end of this months-long process, a large team of chemists and biologists usually deem only 1% or fewer of the compounds worthy of further testing in living cells.

A novel method, demonstrated by Whitehead scientists and described in the July 13 issue of Nature Chemical Biology, uses baker's yeast cells to perform most of the same work in a matter of weeks, with the added benefit that the testing is all done in living cells. At the core of this approach are extremely small proteins, called cyclic peptides, which are capable of targeting the protein-protein interactions found in almost every cellular process. Most current drugs act by wedging themselves into small pockets on the surfaces of target proteins. However, these traditional drugs are unable to adhere to smooth, flat protein surfaces, rendering the drugs ineffective for inhibiting the key interactions among proteins that occur at these surfaces. Cyclic peptides have the ability to bind where traditional drugs cannot, allowing for the identification of previously overlooked targets to fight disease.

"We're getting at a chemical space that is very underexplored by traditional drug development and screening," says Joshua Kritzer, author of the Nature Chemical Biology paper and a postdoctoral researcher in Whitehead Member Susan Lindquist's lab.

"I think it's a very exciting method," says Lindquist, who is also a professor of biology at MIT and a Howard Hughes Medical Institute Investigator. "It provides much greater diversity in the chemical compounds you can study because you can screen millions of compounds in the same go."

Adapting previous work by the Benkovic lab at Pennsylvania State University, Kritzer created a vast "library" of cyclic peptides containing various amino acid combinations. He then inserted the cyclic peptides into cells of a well-established yeast model of Parkinson's disease that was created in the Lindquist lab.

Parkinson's disease is a neurodegenerative disorder characterized by tremors, muscle rigidity, and slowed movements. In the neural cells of Parkinson's patients' brains, researchers have noted Lewy bodies, abnormal aggregates primarily composed of the protein alpha-synuclein. There is currently no cure for the disease, and current Parkinson's therapies only address disease symptoms. In the Lindquist yeast model, the cells exhibit many of the hallmarks of cells in Parkinson's disease patients' brains, including death due to toxic overproduction of alpha-synuclein.

Once the cyclic peptides were inserted into the model yeast cells, Kritzer switched the yeast into Parkinson's mode and waited to see which yeast cells survived. Of the approximately 5 million yeast cells that were inserted with a cyclic peptide, Kritzer ended up with only two cyclic peptides able to rescue the cells from death.

After sequencing them, Kritzer found that both effective cyclic peptides needed only the first four amino acids to work and those amino acids had a common motif (cysteine – any amino acid – a hydrophobic amino acid – cysteine). This particular four-amino-acid motif is very similar to some important biochemical structures, including molecules that oxidize or reduce other molecules and molecules that bind to metals.

Interestingly, there are already links between Parkinson's and the metal manganese. Overexposure to the metal manganese can lead to parkinsonism, a Parkinson's disease-like syndrome. Also, earlier work conducted by Aaron Gitler and Melissa Geddie in the Lindquist lab found that the normal version of the gene PARK9, which can be mutated in Parkinson's disease patients, protects cells from toxic levels of manganese.

With these possible modes of action in mind, Kritzer and colleagues are now trying to figure out how the new cyclic peptides work. Using the Lindquist yeast model and a worm model of Parkinson's disease from the Caldwell lab at the University of Alabama, they confirmed that the effective cyclic peptides have the same potency as natural genes that regulate Parkinson's related cellular processes, but intercept the disease's progress at a later point. This demonstrates that these cyclic peptides act at a point in the disease process that had not been targeted by other, more traditional approaches.

According to Kritzer, who will be starting this September as an Assistant Professor of Chemistry at Tufts University, a next step in this line of research will be to determine precisely how the effective cyclic peptides affect Parkinson's disease cells – by changing reduction or oxidation within the cell, binding to metal molecules, or perhaps another mechanism. In addition, more potent structures may be possible, so the cyclic peptides' known structure can be used as a starting point for more libraries which may produce even more effective versions.

Lindquist also says the technique is not limited to just yeast or just Parkinson's disease. "There's absolutely no reason we couldn't apply the same process to mammalian cells. And it should be applicable to all sorts of diseases that are modeled in yeast," she says. "In fact, that's some of the stuff we've started doing with this technique."

This study was funded by National Institute of Neurological Disorders and Stroke (NINDS), National Institute of Environmental Health Sciences (NIEHS), and the Morris K. Udall Centers of Excellence for Parkinson's Disease Research.

Written by Nicole Giese.

Susan Lindquist's primary affiliation is with Whitehead Institute for Biomedical Research, where her laboratory is located and all her research is conducted. She is also a Howard Hughes Medical Institute investigator and a professor of biology at Massachusetts Institute of Technology.

Full Citation:

"Rapid selection of cyclic peptides that reduce alpha-synuclein toxicity in yeast and animal models"
Nature Chemical Biology, July 13, 2009
Joshua A Kritzer (1), Shusei Hamamichi (2), J Michael McCaffery (3), Sandro Santagata (1,4), Todd A Naumann (5), Kim A Caldwell (2), Guy A Caldwell (2), and Susan Lindquist (1,6).
Whitehead Institute for Biomedical Research, Cambridge Massachusetts, USA.
Department of Biological Sciences, University of Alabama, Tuscaloosa, Alabama, USA.
Integrated Imaging Center and Department of Biology, Johns Hopkins University, Baltimore, Maryland, USA.
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania, USA.

Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge Massachusetts, USA.

Nicole Giese | EurekAlert!
Further information:
http://www.wi.mit.edu

More articles from Life Sciences:

nachricht Transport of molecular motors into cilia
28.03.2017 | Aarhus University

nachricht Asian dust providing key nutrients for California's giant sequoias
28.03.2017 | University of California - Riverside

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: A Challenging European Research Project to Develop New Tiny Microscopes

The Institute of Semiconductor Technology and the Institute of Physical and Theoretical Chemistry, both members of the Laboratory for Emerging Nanometrology (LENA), at Technische Universität Braunschweig are partners in a new European research project entitled ChipScope, which aims to develop a completely new and extremely small optical microscope capable of observing the interior of living cells in real time. A consortium of 7 partners from 5 countries will tackle this issue with very ambitious objectives during a four-year research program.

To demonstrate the usefulness of this new scientific tool, at the end of the project the developed chip-sized microscope will be used to observe in real-time...

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Transport of molecular motors into cilia

28.03.2017 | Life Sciences

A novel hybrid UAV that may change the way people operate drones

28.03.2017 | Information Technology

NASA spacecraft investigate clues in radiation belts

28.03.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>