Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Discovery paves the way for a new generation of chemotherapies

10.09.2014

In an article published in the journal Chemistry & Biology, researchers describe a new mechanism that inhibits the activity of proteasomes, protein complexes that are a target for cancer therapy

A new mechanism to inhibit proteasomes, protein complexes that are a target for cancer therapy, is the topic of an article published in the journal Chemistry & Biology. The first author of the study is Daniela Trivella, researcher at the Brazilian Biosciences National Laboratory at the Brazilian Center for Research in Energy and Materials (LNBio/CNPEM).

The findings of the study, conducted with FAPESP support in partnership with researchers from the University of California in San Diego, United States, and at the Technische Universität München, in Germany, are paving the way for the development of a new generation of chemotherapy drugs that are more effective and less toxic.

"We have already developed a series of molecules based on the newly identified mechanism. Now we plan to synthesize them in partnership with CNPEM researcher Marjorie Bruder and test their potential. The goal is to optimize the proteasome inhibition effect, make the compound even more selective of tumor cells and eliminate the resistance problems found with drugs that are currently available on the market," Trivella said.

A member of the category of enzymes known as proteases, the proteasome is a protein complex responsible for several essential functions inside cells, such as eliminating harmful or non-functioning proteins and regulating the processes of apoptosis (programmed cell death), cell division and proliferation.

In 2012, the drug carfilzomib, inspired by a natural molecule called epoxomicin, was approved. Also in 2012, U.S. and Brazilian researchers isolated a natural molecule in cyanobacteria from the Caribbean called carmaphycin, whose reactive group (the portion of the molecule that interacts with the proteasome) is the same as that of carfilzomib. The molecule is known as an epoxyketone.

"Epoxyketones are very potent selective inhibitors of the proteasome because they interact with this enzyme in two stages: the first reversible and the second irreversible," Trivella explained.

To optimize its effect and find new reactive groups, researchers from the Scripps Institution of Oceanography at the University of California in San Diego developed a series of synthetic analogs with slight structural modifications.

Trivella tested these compounds during an internship in California in her post-doctoral research when she was still associated with the Chemistry Institute at the University of Campinas (Unicamp).

One of the molecules tested had an enone as a reactive group and had characteristics of carmaphycin and another natural molecule named syringolin, isolated from plant pathogens.

By investigating the reaction mechanisms of the new molecule, named carmaphycin-syringolin enone, the researcher verified that unlike syringolin, and thus like the epoxyketone, the enone interacts with the proteasome in two stages, with the second stage being irreversible.

Additionally, Trivella had observed that in the case of the enone, the second reaction occurs more slowly, increasing the duration of the reversible phase of carmaphycin-syringolin enone inhibition.

"Because the irreversible inactivation of the proteasome has toxic effects, the best window of reversibility observed for the carmaphycin-syringolin enone will potentially reduce the toxicity of this new class of proteasome inhibitors," Trivella said. "The compound would therefore present a balance between selectivity and potency."

Toxicity tests are still underway. In parallel, studies have been conducted with the help of crystallography techniques to discover exactly how the interaction between the enzyme target and the carmaphycin- syringolin enone target occurs.

"We discovered that a chemical reaction called hydroamination occurs, which had never before seen under physiological conditions. This type of reaction is frequently used by synthetic chemists in preparing substances, but normally it requires very specific temperature and pH conditions and the use of catalysts to occur. It has never been reported as a mechanism of enzyme inhibition," Trivella said.

Inspired by this new mechanism for proteasome inhibition, the LNBio group plans to synthesize and test a new series of carmaphycin-syringolin enone analogs to determine their effects on the therapeutic window (preferential death of tumor cells in relation to healthy cells) and assess whether they are also capable of reacting with proteasomes that are resistant to traditional inhibitors.

Another of Trivella's goals is to look for natural compounds in Brazilian biodiversity that could serve as inspiration for the design of other categories of proteasome inhibitors.

Samuel Antenor | Eurek Alert!
Further information:
http://www.fapesp.br/

Further reports about: chemotherapies compounds death enzyme irreversible mechanism proteasome reactive

More articles from Life Sciences:

nachricht Symbiotic bacteria: from hitchhiker to beetle bodyguard
28.04.2017 | Johannes Gutenberg-Universität Mainz

nachricht Nose2Brain – Better Therapy for Multiple Sclerosis
28.04.2017 | Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Fighting drug resistant tuberculosis – InfectoGnostics meets MYCO-NET² partners in Peru

28.04.2017 | Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

 
Latest News

Wireless power can drive tiny electronic devices in the GI tract

28.04.2017 | Medical Engineering

Ice cave in Transylvania yields window into region's past

28.04.2017 | Earth Sciences

Nose2Brain – Better Therapy for Multiple Sclerosis

28.04.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>