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 Rainbow colors reveal cell history: Uncovering β-cell heterogeneity
22.09.2017 | DFG-Forschungszentrum für Regenerative Therapien TU Dresden

nachricht The pyrenoid is a carbon-fixing liquid droplet
22.09.2017 | Max-Planck-Institut für Biochemie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: The pyrenoid is a carbon-fixing liquid droplet

Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.

A warming planet

Im Focus: Highly precise wiring in the Cerebral Cortex

Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.

The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...

Im Focus: Tiny lasers from a gallery of whispers

New technique promises tunable laser devices

Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...

Im Focus: Ultrafast snapshots of relaxing electrons in solids

Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!

When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...

Im Focus: Quantum Sensors Decipher Magnetic Ordering in a New Semiconducting Material

For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.

Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

Rainbow colors reveal cell history: Uncovering β-cell heterogeneity

22.09.2017 | Life Sciences

Penn first in world to treat patient with new radiation technology

22.09.2017 | Medical Engineering

Calculating quietness

22.09.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>