Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Molecular staples shape a cancer killer

03.09.2004


Howard Hughes Medical Institute (HHMI) researchers have successfully designed and improved a new type of cancer-killing compound by performing molecular surgery to stabilize the molecule so that it selectively triggers cell death.



The idea for developing the compound emerged from the HHMI laboratory of Stanley J. Korsmeyer, who leads one of the hottest research teams currently studying programmed cell death, or apoptosis, a genetic program that executes cells that are no longer needed. Using the biologically active portion of a protein that triggers apoptosis, Korsmeyer’s team successfully inserted non-natural amino acids into the peptide sequence and then performed a chemical reaction that created a "staple" within the molecule, resulting in its stabilization. Korsmeyer and the paper’s lead author, Loren D. Walensky, who are at the Dana-Farber Cancer Institute at Harvard Medical School, reported their studies in the September 3, 2004, issue of the journal Science.

The chemical approach they applied, called hydrocarbon stapling, was developed by their collaborator Gregory L. Verdine of Harvard University, and permitted the researchers to overcome the tendency of short peptides to lose their critical three-dimensional structure – and their ability to kill cells -- when removed from the context of the complete protein. This has been one of the greatest obstacles associated with using short peptides as therapeutic agents, and has hindered their legitimacy as pharmaceutical lead compounds. By making the peptides more resistant to degradation and enabling their cellular uptake, the hydrocarbon staple overcomes classic shortcomings of peptide therapeutics.


As the molecular events that lead to execution and death have become clearer during the last decade, researchers speculated that it would not be long before biotechnology and pharmaceutical companies were racing to develop novel compounds that could be used to hasten or prevent the demise of cells. "Academic and industrial laboratories are engaged in a Herculean effort to develop new molecules that reactivate the apoptotic program in tumor cells," wrote HHMI investigator Steven F. Dowdy of the University of California, San Diego, in a Perspectives article that was published in the same issue of Science.

Korsmeyer, Walensky, and their colleagues aimed to construct a key regulatory segment of an apoptosis-triggering protein called BID that could induce apoptosis in cancer cells. Their objective was to create a short peptide that functionally mimicked the specific region of the BID protein that elicits cell death. Theoretically, such a small molecule -- basically a short string of amino acids -- could insinuate itself into cancer cells to trigger their suicide. "Our goal was to modify the natural peptide sequence only enough to stabilize or reinforce its shape to improve its pharmacological properties," said Walensky. The researchers used the hydrocarbon stapling strategy to brace the peptide from within.

"We substituted non-natural amino acids for natural amino acids in selected positions," he said. "The non-natural amino acids look very similar to the natural ones, except that they include hydrocarbons that can be cross-linked to one another. This cross-linking provides a constraint, which doesn’t allow the peptide to unfold." The researchers dubbed the engineered peptide "stabilized alpha-helix of BCL-2 domains" (SAHB). The BCL-2 family of proteins regulates apoptosis.

When the researchers examined SAHB’s properties, they found that it assumed a stable alpha-helical shape, bound to the right protein to trigger apoptosis, and resisted degradation by proteases. They also found that SAHB specifically triggered the cell’s power plants, the mitochondria, to release a protein that participates in launching apoptotic destruction.

Their experiments with leukemia cells cultured in the laboratory revealed that SAHB could enter, and, more importantly, inhibit the growth of those cells. "When we saw that we could activate cell death in a specific way in whole cells, we were eager to conduct animal studies," said Walensky. So, the researchers tested the effects of SAHB on mice that harbored human leukemia cells. "We found that SAHB treatment effectively suppressed leukemia in these mice," he said.

According to Walensky, the experiments are the first steps in a broader effort to construct hydrocarbon-stapled alpha-helical peptides that affect many control points of apoptosis. These are necessary because different cancers may have thwarted the apoptotic machinery in different ways, he said. "The goal would be to use the natural sequences of these pro-apoptotic peptides to try to specifically activate the cell death program in a resistant cell," said Walensky. "For example, certain lymphomas are specifically driven by BCL-2 overexpression. So, if you could knock down some of the impact of that BCL-2, you would tip that lymphoma cell over the edge toward death."

Korsmeyer, Walensky, and their colleagues are now developing and testing different hydrocarbon-stapled BH3 domains against a range of cancer cells. Ultimately, they believe that further development of these peptides could broaden the arsenal of compounds used to kill different cancers.

Walensky said he would not be surprised to see hydrocarbon stapling of alpha-helices applied to control many interactions between proteins. "The alpha-helix plays a pivotal role in many biological interactions," said Walensky. "So if we could target protein-protein interactions at critical biological control points using the natural, evolutionarily derived sequence for that protein target -- with just this minor modification of hydrocarbon stapling -- then we might have a whole new set of tools to study and manipulate protein interactions within cells."

Jennifer Michalowski | EurekAlert!
Further information:
http://www.hhmi.org

More articles from Life Sciences:

nachricht Researchers identify potentially druggable mutant p53 proteins that promote cancer growth
09.12.2016 | Cold Spring Harbor Laboratory

nachricht Plant-based substance boosts eyelash growth
09.12.2016 | Fraunhofer-Institut für Angewandte Polymerforschung IAP

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Electron highway inside crystal

Physicists of the University of Würzburg have made an astonishing discovery in a specific type of topological insulators. The effect is due to the structure of the materials used. The researchers have now published their work in the journal Science.

Topological insulators are currently the hot topic in physics according to the newspaper Neue Zürcher Zeitung. Only a few weeks ago, their importance was...

Im Focus: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

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

14.10.2016 | Event News

 
Latest News

Researchers identify potentially druggable mutant p53 proteins that promote cancer growth

09.12.2016 | Life Sciences

Scientists produce a new roadmap for guiding development & conservation in the Amazon

09.12.2016 | Ecology, The Environment and Conservation

Satellites, airport visibility readings shed light on troops' exposure to air pollution

09.12.2016 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>