Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Optimizing protein’s ’death domain’ halts leukemia in laboratory study


Spiral-shaped molecules, reinforced by chemical ’staples,’ could aid drug discovery

A part of the system that causes cells to self-destruct when they are damaged or unneeded has been harnessed to kill leukemia cells in mice, say scientists at the Dana-Farber Cancer Institute. The discovery could aid in the discovery of new drugs for cancer and other diseases. The researchers plucked a critical "death domain" from a key molecule in the self-destruction mechanism of a cell, stiffened its Slinky-like structure with chemical "staples," and used it as a highly specific weapon to destroy leukemia cells. The findings will be published in the Sept. 3 issue of the journal Science.

"We have demonstrated an approach for getting at potential new drugs by using natural sequences [of amino acids] that have known biological effects," says Stanley J. Korsmeyer, MD, of Dana-Farber, co-senior author of the paper. "In this case we took the critical killer domain out of a pro-death molecule and chemically reinforced it, so we were able to get it into cancer cells and kill them."

Loren D. Walensky, MD, PhD, of Dana-Farber and Children’s Hospital Boston is the paper’s first author and Gregory L. Verdine, PhD, of Harvard University, is co- senior author.

Korsmeyer and his colleagues have pioneered studies of apoptosis, or programmed cell death, that rids the body of damaged or unneeded cells. Apoptosis is directed by a complex collection of proteins in a yin-yang-like balance and is activated by a variety of external and internal signals. Some of the proteins set in motion a cell’s death, while other "survival" proteins act to prevent programmed cell death.

One hallmark of cancer is that an excess of anti-death or survival proteins overwhelms the system when it is trying shut down the abnormal cell, causing the cell to reproduce, dangerously out of control, when it should be dying.

The pro-death part of the apoptosis toolbox includes a number of molecules known as BH3-only proteins. To ensure that cells destroy themselves when appropriate, despite contrary signals from anti-death molecules, BH3-only proteins contain a peptide subunit, termed "BH3", that is made of amino acids and functions as a critical "death domain." This subunit forms a coiled structure called an "alpha helix," which is similar to the shape of a Slinky toy. Amino acids positioned on the surface of the coils bind to amino acids on anti-death molecules such as BCL-2 and inhibit their activity. BCL-2, a key part of the apopotosis mechanism, was discovered by Korsmeyer.

Building on other recent work, Walensky sought to remove the alpha-helical BH3 subunit from the protein and use it as a sharply aimed tool to shut down the BCL-2 protein and activate the death pathway in cancer cells, without harming normal cells. If that proved successful, it would show that the BH3 alpha helix – and alpha helices from many other proteins – could be used like keys to turn off protein activity involved in disease processes.

These alpha helices then could serve as the foundation for building novel drugs. But one hurdle loomed. When the helical "death domain" is removed from its parent protein, it loses its rigid shape, becoming floppy liked an overstretched Slinky. In this form, it is vulnerable to degradation, unable to enter cells, and left powerless to block the antideath BCL-2 protein. Walensky’s goal was to return the isolated amino acid helix to its original shape after its removal from the BH3-containing protein.

Drawing on his dual background in chemistry and cell biology, and applying a strategy developed by Verdine, who is a chemist, Walensky found the answer. First, he made synthetic amino acids that mimicked some of those within the helix. "Then we swapped out the natural amino acids and inserted the synthetic ones" at certain positions along the helix. Crucially, the artificial amino acids were linked to each other by a pair of hydrocarbon subunits. Like a reinforcing metal staple, Walensky explains, these links held the peptide in its natural coiled configuration.

Further experiments confirmed that the stapled BH3 alpha helix retained its biological activity. In fact, it bound even more strongly to its target on the BCL-2 molecule, blocking its activity. Moreover, the reinforced coil was able to enter cancer cells and trigger apoptosis, or self-destruction, of those cells.

The most dramatic success occurred in mice transplanted with leukemia cells that gave off a glow when the mice were injected with a light-emitting substance, luciferin. After they administered the reinforced BH3 alpha helices, scientists noted that the glowing regions representing the leukemia cells retreated as the cells died, and the treated mice survived longer than those that were untreated.

"By applying a new chemical approach, we were able to brace peptides from within to generate biological tools that hadn’t existed before," says Walensky, "and these new molecules directly inhibit a protein interaction that we’re interested in. The potential is that you could take any alpha helix involved in a pivotal protein interaction, relevant to cancer or other diseases, and target it to that protein to disrupt the disease process."

Bill Schaller | EurekAlert!
Further information:

More articles from Life Sciences:

nachricht Sweetening neurotransmitter receptors and other neuronal proteins
28.10.2016 | Max-Planck-Institut für Hirnforschung

nachricht A new look at thyroid diseases
28.10.2016 | Jacobs University Bremen gGmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Etching Microstructures with Lasers

Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.

This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...

Im Focus: Light-driven atomic rotations excite magnetic waves

Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion

Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

How nanoscience will improve our health and lives in the coming years

27.10.2016 | Materials Sciences

OU-led team discovers rare, newborn tri-star system using ALMA

27.10.2016 | Physics and Astronomy

'Neighbor maps' reveal the genome's 3-D shape

27.10.2016 | Life Sciences

More VideoLinks >>>